On June 12, 2013, twelve ME/CFS patient organizations and 23 patient advocates signed a letter calling for an immediate investigation into threats made against three members of the CFS Advisory Committee (CFSAC). The letter was written in response to events that occurred on the second day of of the CFSAC meeting (May 23rd). During the meeting, patient advocate Eileen Holderman, after repeated attempts on the part of the chair to silence her, stated that she was "afraid." Holderman went on to say, "I have been intimidated, and I’m afraid to speak out but I am going to. I know that there are two other committee members who have also gotten calls." A short time later, researcher Mary Ann Fletcher stated that she had been threatened with eviction from the Committee for expressing her views.

Federal Advisory Committees were established to help the executive branch formulate federal policy. The CFSAC was created to advise the Secretary of Health on issues such as healthcare, the science and definition of CFS, and other issues related to the disease. Over the last decade, CFSAC has made more than 70 recommendations to the Secretary on a number of issues, including research funding, provider education, case definition, and a name change. According to Holderman, the CFSAC has acted on none of them.Although the CFSAC operates at the behest of the federal government, it has come under fire for violations of the Federal Advisory Committee Act, including acting in secrecy to reduce or reword recommendations made by committee members. (Read about the violations in Jennie Spotila's article HERE.)

You can read the full text of the letter below. A transcript of the portion of the meeting including Holderman's allegations can be read HERE. You can see video of this portion of the meeting HERE. (Start at 42:12)

On behalf of the undersigned organizations and individuals, I am writing to request your immediate investigation into alleged intimidation of three voting members of the Chronic Fatigue Syndrome Advisory Committee (CFSAC), a Department of Health and Human Services advisory committee housed within the Offrce on Women’s Health. As organizations and advocates serving patients with Chronic Fatigue Syndrome (CFS), we have a longstanding interest in federal policy regarding CFS.

At its most recent public meeting on May 23,2013, voting member Eileen Holderman stated that Dr. Nancy Lee, the Committee’s Designated Federal Officer (DFO), had intimidated her and two others. Voting member Dr. Mary Ann Fletcher stated that she had been threatened with eviction from the Committee for expressing her views. The third member subjected to the alleged intimidation was not identified. We have enclosed a transcript of portion of the meeting during which these allegations were made, and highlighted the allegations on pages 3 and 4.

The independence of the CFSAC and the balance of views among the membership are essential to its advisory role. Threats or intimidation of voting members for expressing their views, particularly by the DFO, would materially impair the CFSAC’s ability to formulate recommendations to the Secretary. Despite the seriousness of these allegations, neither Dr. Lee nor Chairman Dr. Gailen Marshall made any public comment, nor did they promise to look into the allegations or take corrective action.

Therefore, we must ask you to investigate these allegations immediately, and establish whether any voting member of the CFSAC has been intimidated or threatened for expressing their opinions.

Just hours before the FDA's April 25th workshop, "Drug Development for Myalgic Encephalomyelitis and Chronic Fatigue Syndrome," Drs. Dan Peterson, Derek Enlander and Nancy Klimas, three CFS/ME specialists with long experience in both treating and researching the illness, held a meeting of their own. Here Cort Johnson reports on what was discussed in that meeting. To read the full report go to the Simmaron website here.

Diagnostics always come first. Before you can treat you must be able to diagnose. Unfortunately the diagnostics in chronic fatigue syndrome have been shrouded, vague, symptom-based definitions. From the myalgic encephalomyelitis to the Holmes to the Fukuda to the Canadian Consensus Criteria, the chronic fatigue syndrome field has been grasping for definitions for as long as it’s been around.

Problems on the macro level (the definition), of course, lead to problems at the micro level ( the doctor’s office) where ME/CFS doctors are deluged with all different kinds of ‘chronic fatigue syndrome’ patients. That uncertainty – not knowing just who might step in the door –surely makes for an interesting job. The qualifications for a good chronic fatigue syndrome physician may look something like this…. good listener, not daunted by complexity, loves to problem-solve, has a wide range of knowledge and is flexible and willing to try new things.

As Bernard Munos pointed out at the FDA Workshop, in a disorder like this, which has few clinical trials, the physicians, more than anyone else are the innovators. Not able to rely on clinical trials, their offices are an ongoing clinical trial.

Given the many different types of patients Dr. Peterson sees, the idea of drug trials that don’t establish subsets first is simply appalling. The idea that this complex mix of patients are ever going to respond similarly to a drug is nonsense.“I am very concerned about random drug trials that take the first 100 patients who sign up. It would be a disaster,” said Dr. Peterson.

For Dr. Peterson, who sees the complexity of the illness daily, diagnosis, whether in a research study, clinical trial or a doctor’s office, always comes first. Since the same symptoms can be produced by many different factors, symptom definitions, while helpful, will always have flaws. What’s needed is to ‘scientifically redefine ME/CFS’; that’s the Simmaron Foundation’s stated goal and each of these physician/researchers is working towards that.

How to Diagnose ME/CFS: The Immune System

Dr. Peterson started off by stating that after screening for the ‘obvious stuff’ he goes after immune markers, primarily focusing on the NK, T and B cells.

Over time he found consistent patterns began to emerge with natural killer (NK) cells playing a major role. (These cells, which play a major role in the early, innate immune response, appear to be ground zero for the immune problems in ME/CFS. Unfortunately, they’re not particularly well known in the medical community. Dr. Peterson’s poll of his colleagues in his area a couple of years ago found that few knew anything about them.)

It doesn’t help that natural killer cells are tricky to work with and need to be assessed within four to six hours of sample collection. In an attempt to make them more user friendly, Dr. Peterson is experimenting with freezing live cells in liquid nitrogen.

As an immunologist, it wasn’t surprising to see Dr. Klimas’ strong focus on the immune system. With one of the top immune labs in the country, Dr. Klimas is at the center of a lot of immunology work on CFS/ME.

Immune factors are one lab measurement that has to be accurate; tweak the powerful immune system the wrong way and you can cause a lot of trouble. If the physician is using immune altering drugs, and both Dr. Peterson and Dr. Klimas do, the ability to trust your lab is critical. Dr. Klimas said her immune lab is the ‘gold standard’ and Dr. Peterson gets all his cytokine arrays done at Dr. Klimas' lab.

Dr. Klimas will dig into IGG subclasses if she sees bacterial infections. Dr. Enlander focuses on much the same factors; CD4 and 8 ratios, NK cells and function, (IL2, IL4, IL10) and uses bacterial cultures to rule out other disease entities, like Lyme, etc.

Pathogens

Pathogens were discussed briefly. All three physicians were testing for them (eg; EBV, HHV6, CMV, Parvovirus, Coxsackie and bacteria), but there were some differences. Dr. Enlander did not see a relationship between viral load and disease severity, something that Dr. Peterson, as we’ll see later, has found, at least with one group of patients. Dr. Klimas has not found HHV6 to be a good marker either, as patients don’t test positive consistently; in fact, she called ME/CFS a ‘good-day, bad-day viral disease’ as patients may test negative on a good day and positive on a bad one. That’s helpful for her as a physician but is not good enough for the FDA to test treatments against. The FDA needs a test that’s consistently positive.

What does Dr. Klimas find that correlates with severity?

Natural killer cell functioning and IL-5 levels might be two markers the FDA could use to assess treatment effectiveness.

We don’t hear a lot about IL-5 but it boosts two immune factors of interest in ME/CFS; mast cells and B-cells. Overactive B-cells have been implicated in autoimmune disorders and, of course, also harbor EBV as well.

Dr. Enlander will be seeking to confirm/deny Dr. Chia’s enterovirus findings in his exercise study.

Autonomic Nervous System

After Dr. Peterson stated that the amount of autonomic nervous system dysfunction in ME/CFS was ‘huge,’ the stage was set for the autonomic discussion. All three doctors do blood pressure and pulse testing. Dr. Peterson and Dr. Enlander do 24-hour BP and heart testing, and Dr. Enlander and Dr. Klimas use tilt table testing. Dr. Klimas noted that autonomic nervous system dysfunction appears to trigger immune dysfunction. She asserted that the sympathetic nervous system is a major player in this disorder and she rattled off problems with standing, respiration, poor digestion, etc. that could all be caused by SNS upregulation.

It’s not clear how many of the physicians were measuring blood volume; it may be that they all simply assume blood volume is low. Dr. Klimas noted the astounding fact that most patients are about a liter of blood low, or about 20% down from normal. With that little blood running through your blood vessels those blood vessels are going to have to squeeze hard to get it out to the tissues and brain, and right there you have a good reason for the sympathetic nervous system activation Dr. Klimas talked about earlier.

Dr. Klimas gives blood volume a boost with electrolytes and then puts the patients back on the tilt table to see if they’ve improved.

Dr. Enlander is using Dr. Cheney’s cardiac protocols to measure cardiac output, stroke volume, etc. He does it, interestingly enough, in a variety of positions (lying down, standing) giving him a great deal of data on cardiovascular functioning.

Aerobic Testing

You probably couldn’t get three ME/CFS physicians more knowledgeable or committed to exercise testing in one room than you had at the Roundtable.

As the first ME/CFS physician to embrace VO2 max testing, Dr. Peterson made a strong plug for Staci Stevens' two-day exercise test protocol (the Stevens Protocol. This exercise test grew out of the work she did in Dr. Peterson’s office).

Dr. Peterson uses the most rigorous test of all; the aerobic exercise test to determine how well his interventions are working. At the FDA Ampligen hearing, Dr. Bateman noted that the VO2 max test, which measures the amount of energy a person can produce, is the hardest to improve of all ME/CFS tests. Since Dr. Peterson finds that low VO2 max scores are often correlated with poor cognition, abnormalities on MRIs and spinal fluid as well as autonomic problems, bumping up those VO2 max scores even moderately can mean a significant improvement in functionality and well-being.

All three practitioners use exercise testing in for research, disability and/or to assess the effectiveness of their interventions

( I asked Staci Stevens if she knew of any ME/CFS patients who had returned to full VO2 max functioning and she said yes, some patients on antivirals and Ampligen had returned to full VO 2 max functioning.)

Dr. Klimas has been digging deep into exercise in her research, which, in turn, is informing her diagnostic work. (This is known as ‘translational medicine’). Earlier this year she reported gene expression studies indicating that the autonomic nervous system drops first during exercise and then drags the immune system down with it.

This major finding, if validated, suggests breakdowns in the ANS, which is tightly intertwined with the immune system, could be at the core of the disorder.

Dr. Enlander is committing a big chunk of money to a sophisticated exercise testing study at the Mt Sinai Research Center. He’s has a geneticist, an immunologist and a pulmonologist all working together.

After having patients exercise, Enlander’s team will be looking at RNA (genes), blood (immune factors, a stool sample, RNA, DNA genome, enteroviruses), brain MRI and SPECT scans. Among other things Enlander will be looking to confirm or deny Dr. Chia’s findings seven years ago of enteroviral infections in CFS/ME patients.Spinal Taps and Brain ImagingDr. Peterson does spinal taps to figure out what’s going on with his most cognitively challenged and neurologically impaired patients. (After decades of gathering spinal fluid, Dr. Peterson easily has the greatest store of ME/CFS spinal fluid on the planet. Dr. Mady Hornig has referred to Dr.Peterson’s spinal fluid as a "precious resource.")

Spinal taps are where Dr. Peterson, Dr. Klimas and Dr. Enlander part ways to some extent. Both Klimas and Enlander do them at times, but Dr. Peterson does them routinely in patients with neurological and brain issues (and he does them himself). Dr. Klimas said she was astounded that Dr. Peterson found 17% of his patients’ spinal fluid tested positive for a virus.Both Drs. Klimas and Enlander may be doing spinal taps more in the future. Dr. Klimas is waiting to find the right neurologist, and Dr. Enlander said he was closely following Peterson’s ideas. If the CFI and PHANU studies using Dr. Peterson’s spinal fluid are positive, we may see more and more doctors turning to spinal fluid to assist with their diagnoses.Dr. Peterson looked forward to future medical advances that will help him fine tune his diagnostic protocols. Genetic technologies are indicating, for instance, that a genetic predisposition to the NK dysfunction may be present in ME/CFS. On the other hand he also finds ‘acquired’ (i.e. non-genetic) NK cell dysfunction as well. He believes insights gathered from mRNA in the spinal fluid of ME/CFS patients, for instance, and more rigorous pathogen detection techniques will continue to open up this field and inform his diagnostics.Similarly, Dr. Klimas’ exercise studies are leading her to focus more on improving autonomic dysfunction in her patients. Dr. Enlander will use his big exercise study to increase his understanding of his patients. Each of these three physician/researchers is eager to incorporate their research findings into their diagnostic protocols.Undefining ME/CFS?“There is an entire school of thought in the medical profession that if anyone with chronic fatigue has anything objectively wrong with them – they don’t have chronic fatigue syndrome.” Dr. Dan PetersonAfter all the talk about how to diagnose ME/CFS, Dr. Peterson brought up a trend towards ‘undefining’ that he found troubling. Undefining ME/CFS consists of putting ME/CFS patients in a different category as soon as something concrete is found. Stating that this attitude is now prevalent, Dr. Peterson explained that a person with ME/CFS with HHV6A in their spinal fluid will be labeled as having HHV6A encephalitis and be determined to never have had ME/CFS.

Dr. Klimas acknowledged that while getting a diagnosis that can be treated is great, culling out large numbers of ME/CFS patients could be devastating. For one, it condemns ‘ME/CFS’ to be a a mere placeholder of an illness.

Dr. Klimas noted that Dr. Peterson’s finding that 17% of his cognitively dysfunctional patients were culture positive for viruses in their spinal fluid comprised a clear subset. (She was reminded of former CDC CFS chief Bill Reeves' response “you don’t know what doesn’t belong there.” She laughed and said, “Wait a minute. Would it be okay for you to have your cognitively dysfunctional child have a positive spinal fluid test? I don’t think so.”) What a dilemma, she said, that every time we start to get clarity, part of this disorder gets shuffled off into another column.The Hidden Epidemic“Talk about a forgotten, ignored group of people.” Dr. PetersonThen there are the missing patients; the bedridden ones who rarely get to doctors' clinics and certainly aren’t in research studies. How do you define a disease without access to all the patients? In most disorders, the most severely ill usually get the most attention, but the opposite is true in ME/CFS. (A former ICU nurse working with Dr. Kogelnik remarked that these patients should be in a hospital, not at home.)Dr. Peterson“The bedridden patients – It’s the hidden epidemic within another epidemic. It’s scary.” Dr. Dan PetersonDr. Peterson noted that we don’t have an accurate count of how many people are in this situation. He didn’t have answers. He noted that you needed staff to get to these people and you needed to find them in the first place. Dr. Klimas suggested that funds were at the heart of the problem. Ads for an online CBT study did bring in bedbound patients who were unable to make it to the clinic, and funding for the ‘good-day/bad-day’study did allow them to make house calls during patients' bad days. Both Dr. Klimas and Dr. Enlander said they do house calls from time to time.

This article appeared on June 12, on the UK Human Rights Blog. Mr. Courtney's unsuccessful attempt to gain access to the full results of the PACE trial raises two important points: 1) While the write-up in the Lancet claimed that there was an improvement in patients with ME/CFS after treatment with GET and CBT, it intentionally failed to mention the number of patients who got significantly worse on each treatment during the trial, and 2) When full results from a medical trial are withheld from the public, how does that affect the right of patients to know if a therapy might potentially harm them?Freedom of information and unpublished data from a randomised controlled trial on ME/CFS By David Hart, QC"Between 2005 and 2010 Queen Mary ran a trial into the efficacy and safety of the current treatments for Chronic Fatigue Syndrome/Myalgic Encephalopathy, namely Adaptive Pacing Therapy , Cognitive Behaviour Therapy and Graded Exercise Therapy. £5m of public money was spent, and the perceived benefits (and some of the detriments) were written up into a major article published in the Lancet in March 2011. The upshot, said this article, was that CBT and GET could be safely added to current medical care with a moderate improvement in outcomes. This recommendation has already fed into an interim review of the NICE guidelines on CFS/ME.However, the data on deterioration within the trial had not been fully published. You could not see how many patients deteriorated in response to each therapy, just the net deterioration over the whole cohort. Our appellant, Mr Courtney, is evidently a bit sceptical about the results of this trial. As he pointed out, the deterioration data had a 20 point difference, whereas the improvement had only to be modest – an 8 point difference. And, he said, how can patients sensibly form a view on treatment without knowing how much deterioration that specific treatment might cause?So Mr Courtney asked for a full set of the deterioration data for each therapy. Queen Mary sought to withhold it on the basis of section 22 of the Freedom of Information Act 2000– information intended for future publication. And, after a hiccup before the Information Commissioner, they succeeded before the FTT."Like most of the exemptions in Part II of FOIA, withholding the requested information must be shown to be in the public interest. So, given that (a) the data existed and (b) the main trial results had already been published, what on earth was the public interest in withholding it, however temporarily?QM said that, because they had undertaken the work which generated the raw data, they should have the opportunity to present in the context of a full scientific commentary tested by peer review. Conversely, premature publication of provisional research results “particularly if made in a lower ranking journal” might undermine the credibility of the final conclusions. (Here we are very much in the territory of the UEA climate change scientists not wanting the sceptics to get the raw data before UEA has said its piece). Without peer review, QM would be “casting clinicians and patients adrift” – “the data could be manipulated”‘; there is a need for “sufficiently robust scientific contextualisation.”There is something in all of this, but it is also a little bit over the top. It is quite understandable that the researchers might want a short priority period for publication of their research. But their wishes should not be driven by the desire of private top-ranking journals to have an exclusive on the data – as Mr Courtney rightly argued, that is a matter of private interest, not public interest.The FTT found for the University. The additional time sought by it was necessary to finalise the analysis, commentary and peer review process. Hence, the withholding of this data fell within section 22 and was in the public interest.This sort of issue does not seem to have come before the FTT or the courts before. There is an Information Commissioner’s decision on section 22 (see here) where, one infers, a rival academic wished to get hold of a PhD student’s thesis deposited with Liverpool University – the application was refused. The PhD student wished to publish the thesis in book form, and wanted a period in which to see if she could do so. The public interest was rather limited; the student had privately paid to do the PhD, so unlike the QM case, public money was not involved. The IC decision is also very coy about the nature of the thesis, so one cannot tell whether it is of wider public or narrowly academic interest. On the other hand, one cannot be too sorry that the applicant lost, given the more general interest in wider academic publication of scholarly work – better that it be in a published book rather than in a university archive.One final observation. QM nearly got itself into trouble in this case because of its curious publication strategy. It is odd to publish research about the merits of a given set of treatments, without having finalised one’s analytical work on the therapy-specific demerits. From a medical ethics perspective, I wonder to what extent the clinicians and patients appreciated that to some extent the 2011 Lancet publication was work-in-progress – because that is the implication of QM’s arguments on this appeal."

The focus of the first afternoon session was on designing clinical trials for drugs to treat CFS/ME, drawing on the experience of CFS/ME researchers and physicians.You can read a summary of Day One, April 25th, HERE.You can read a summary of Day Two: Morning Panels HERE.You can read a transcript of the April 26 sessions HERE.Panel 3: CFS and ME Clinical Trial Endpoints and Design (158:05) (VIDEO)Moderators: Jordan Dimitrakoff, M.D., Ph.D., Assistant Professor, Tufts University, Boston, MA and Edward M. Cox, M.D., M.P.H., Director, Office of Antimicrobial Products, OND, CDER, FDA

Ashley F. Slagle, MS, PhD, Oak Ridge Institute for Science and Education (ORISE) Fellow, Study Endpoints and Labeling Development Staff, ONDIO, CDER, FDA (contractor)First Speaker: Dr. Peter Rowe, “Clinical Trial Design in CFS.” [timestamp 7:10 – 48:09]Dr. Rowe drew upon his experience over the past 20 years as a CFS researcher and clinician. He addressed several important issues pertaining to clinical methodology: what has and has not worked in clinical trial design, ideal patient populations, ideal endpoint, and potential study designs that might decrease the confounding effects of the heterogeneity of the illness, and which might help identify an effective therapy against the background noise of other comorbid conditions.

Main themes of Dr. Rowe's talk:

Heterogeneity: Because CFS is so heterogeneous with variable onsets, and types of symptoms, as well as different combinations of comorbid conditions, heterogeneity needs to be taken into account when designing a trial for effective therapies. Design problems are the following: Careful selection of groups and subgroups, including those who recently have contracted CFS versus those with established symptoms, how to include patients with different levels of severity. And as with any illness with a lot of heterogeneity, small studies are almost certainly doomed to failure from the outset. We will need large studies to identify clinically significant but modest differences between patients.

Outcome measures that are currently in use are fairly serviceable. Imperfections in measurement tools are not the biggest impediment, but outcome measures need to remain simple.

Trial design: If trials are designed properly, they can yield clinically useful data.

Success and failure of previous clinical trials: Some historical lessons

The first of the modern trials was Strauss’ acyclovir study in 1988 (“Acyclovir treatment of the chronic fatigue syndrome. Lack of efficacy in a placebo-controlled trial.”). It had been hypothesized that CFS was due to a persistent Epstein-Barr viral (EBV) infection. In this study each patient received either acyclovir or placebo. Outcomes included measures of daily energy, how people felt, temperature, and mood. Of the 24 who completed the study, 21 rated themselves as improved, but improvement was evenly distributed among the placebo and acyclovir. (As an aside, Dr. Rowe noted that this was one of the few CFS studies in which there was a high placebo response. Usually CFS patients exhibit a low placebo response.)

In spite of its failure to prove that acyclovir was an effective treatment, Dr. Rowe noted certain design features in the acyclovir study that should be used in current trials, namely crossover design (patients acted as their own controls by taking both the drug and the placebo), culling the study population to increase the likelihood of enrolling those who would most benefit from the intervention, insisting on a clinical evaluation to confirm diagnosis, and simple outcome measures. Although this trial was not a success, it revealed that while a small study could not determine what was effective, it could reveal the negative effects of medications. (Some measurements were actually worse during the acyclovir phase of the trial. i.e. mood and wellness). This is valuable information for future studies.

By 2006 there were 56 randomized trials and 14 non-randomized clinical trials for CFS. These included behavioral interventions (e.g. GET and CBT), immunological treatments (e.g. acyclovir, IVIG, imunovir), corticosteroids (e.g. Florinef, hydrocortisone), various pharmaceuticals (e.g. galantamine, NADH) and complementary therapies (e.g. massage, carnitine, liver extract). The outcome of nearly all these studies has been that pharmaceutical interventions are not helpful.

Why haven’t these trials shown that drugs can be effective therapies for CFS? Dr. Rowe pointed out that the main problem with these studies is methodology. Unless the patients share the same type of onset (sudden or gradual) and similar comorbidities (such migraines, IBS, allergies, orthostatic intolerance, to name a few), the studies run the risk of comparing apples to oranges.

How can heterogeneity be reduced?

Careful subject selection. Clear case definition and clear eligibility criteria need to be established for subsets under study. If subsets are not identified, a predominant comorbidity, for example, can skew the results.

Identifying comorbid conditions. Flares in comorbid illness have the potential of obscuring treatment effects, especially in small samples. These fluctuations can overwhelm the effect of the treatment under study.

Large sample sizes. Given the heterogeneity of CFS and OI, large sample sizes are required, unless there is a powerful medication that applies across all subgroups.

Dr. Rowe stressed the advantage of large sample size by pointing out that while many CFS/ME studies were done using between 12 and 35 patients, the fibromyalgia study of pregabalin enrolled 529 patients. The outcome was simple: pain. Using a daily pain scale, they were able to show that 21% had more than 30% improvement in pain. This study shows that a large sample allows researchers to find results that are clinically significant for a small population.

Dr. Rowe also discussed the PACE trial in terms of its methodological success (with the quip that anyone who ventures into a discussion of the PACE trial probably needs an armed guard). Because the size of the trial was so large – 641 participants – the study showed a small but statistically significant difference (3 points). To put this in perspective, Dr. Rowe said that as physicians, a three-point difference in the Chalder Fatigue Scale (33 points) over a year would be enough to make them hang up their licenses and quit. But, he added, whatever our views are on CBT, it is important to focus on the methods lesson: the study was positive based on the sample size.

Dr. Rowe went on to discuss the Florinef trial conducted in 2001 (“Fludrocortisone acetate to treat neurally mediated hypotension in chronic fatigue syndrome: a randomized controlled trial.”). The study was based on Dr. Rowe’s clinical observations of several patients who had made startling improvements while on Florinef.

The study concluded that there were no significant differences between placebo and Florinef. However, when Dr. Rowe re-examined the results, he found that younger patients and those with a shorter duration of illness had responded to the drug, while patients who had been sick longer than three years had not. The failure of the Florinef study was due to lack of selectivity in patient selection. Additionally, Dr. Rowe pointed out that the success of the PACE trial may have been in part due to selecting for a patient group which had not had a long duration of the illness (2.7 years average). He compared this to the rituximab study which used patients who had been ill for a much longer period of time (5.8 years average).

What is the ideal endpoint?

In his discussion of the rituximab study, Dr. Rowe pointed out that results need to be measured within the context of specific outcomes: cognitive improvement, activity, and functional measures. Simply asking patients how they feel compared two weeks ago is not an accurate measure of improvement, because patients will increase their level of activity as they get better, generating the same level of fatigue. “We’ve got to watch that we don’t use fatigue as the only outcome measure.”

Dr. Snell reported on the value of cardiopulmonary exercise testing (CPET) to establish endpoints in CFS/ME studies. The beauty of exercise testing is that it measures function. Before CPET, nobody had an objective measure of fatigue. Simply asking people how tired they are is not real science. Dr. Snell believes the exercise test is a biomarker for CFS/ME because it provides both diagnostic and prognostic data.The definition of fatigue is reduced efficiency as a result of doing work.People are energy-producing machines with a built-in ability to stretch that energy when needed through the fight or flight response. Disease states reduce this capacity. But, even in disease states, in the absence of stress, reduction in functional capacity isn’t always seen. Exercise is an effective way to induce stress. Once stress is created, the true functional capacity of an individual can be objectively measured.The goal of exercise testing is to assess the function of the cardio-respiratory system.

The way we produce energy is through the cardio-respiratory system, so we need to look at how efficiently that system operates. The cardio-respiratory system determines your functional capacity – or how much work you can do. This system functions on aerobic capacity – that is, how efficiently is the body able to use oxygen?

There are two main energy liberation systems: aerobic and anaerobic.

Aerobic metabolism – dependent on oxygen, is very efficient, can be used for extended periods of time, predominates at lower workloads, produces CO2

VO2 Max is peak oxygen consumption. This is the maximum amount of oxygen a person’s system can deliver in order to produce energy.

Anaerobic threshold: the point at which a person switches from aerobic to anaerobic metabolism.

Both VO2Max and anaerobic threshold can be measured directly using gas exchange techniques and measuring blood lactate levels. Indirect measurements include heart rate and fatigue onset. Indirect measurements are not reliable. They don’t apply in disease states. Indirect measurements, such as field tests (e.g. the 6-minute walk) are also highly subject to bias. They can be influenced by motivation, the attitudes of the testers, and other factors.As a case in point, Dr. Snell offered an interesting analysis of PACE trial. In the PACE study the 6-minute walk field test went from 341 at the beginning of the study to 414 yards a year later. Dr. Snell calculated the mph (miles per hour) as 1.9 at the beginning to 2.3 mph at the end. According to tables used to measure cardiac capacity, walking 6 minutes at 2 mph translates as severely disabled. Dr. Snell does not consider “severely disabled” to be an adequate endpoint for a trial, especially after 52 weeks of graded exercise. Because the improvement was so small, he attributes it to an increase in motivation.

How VO2max is calculatedAerobic metabolism burns oxygen (O2) and releases carbon dioxide (CO2). Once CO2 exceeds O2, the person is approaching his or her maximum capacity. Aerobic metabolism is strongly dependent on the heath of the circulatory system. Anaerobic threshold is measured using gas exchange. If the ratio exceeds more than 1.1, the person’s CO2 is exceeding O2, which means that person is getting close to his or her limit.

Because breathing is involuntary, this result cannot be faked. Gas exchange is therefore a much more accurate measurement than field tests.

Workwell test results for CFS/ME patientsDr. Snell’s group was not able to distinguish CFS patients from controls until they looked at the results of the exercise. People with CFS were sick after the test. Strikingly, their ability to utilize oxygen decreased on the second day of testing. Controls were able to utilize oxygen better on the second day. Later, this study was replicated using 56 patients. While the results were not as dramatic, the second larger study showed that there was a big drop-off in efficiency. CFS patients produced less work for more effort and had a greater buildup in lactate.Summing upPost exercise morbidity distinguishes deconditioning from CFS. CPET is a valid and accepted form of testing - there are just over 400 clinical trials around the world that currently include CPET (clinicaltrials.gov) - and should be used as an endpoint to evaluate the efficacy of any drug treatment in clinical trials.Third speaker: Dr. Elizabeth Unger, “Measures of CFS in a Multi-site Clinical Study.” [timestamp 86:04 – 107:43][For additional coverage of Dr. Unger's talk, see the HealthRising article by Simon McGrath.]Dr. Unger talked about a new CDC study that is currently gathering data to help define subgroups in CFS/ME. The study utilizes patient data from seven participating clinics: Drs. Natelson, Lapp, Bateman, Peterson, Klimas, Kogelnik, and Podell. Specifically, the CDC study addresses the main characteristics of heterogeneity: duration of illness, severity, comorbid conditions, medications and demographics. This study differs from previous CDC studies in two respects 1) it was designed to capitalize on the experience of the clinicians who treat CFS/ME, and 2) it collects standardized data to evaluate the heterogeneity of CFS patients across practices in order to revise the case definition and define subgroups.The data gathered from the CDC study were generated via a physical exam, patient questionnaires – pain, sleep, depression and anxiety scales, CDC symptom inventory, and the DePaul symptom inventory (DSQ) – data extraction from medical records, patient illness history, tests, family history, and infection/immunization history.

First analysis of data from 393 patients in seven clinics (with variation between clinics):Overall demographics:

75.4 % not working (15.4% with unemployment benefits)(this was the only statistic that did not vary between clinics)

Illness onset

Mean age at diagnosis 38.2 years

Sudden onset 66.7% (with variation between clinics)

Mean duration of illness 15 years

Dr. Unger stressed that the patient population in this study is not necessarily representative of the CFS/ME population as a whole. For example, the vast majority of patients were white and insured, which does not correlate with demographic findings of Jason et al., in which CFS/ME was shown to have a high prevalence in non-white populations. Dr. Unger pointed out that this is an indication of lack of access to care that needs to be addressed.

Symptoms resultsFatigue scores varied not only between clinics, but between various instruments used to measure types of fatigue. Of note was the fact that using the general fatigue scale, 37% of the participants scored at the maximum range.The SF-36 questionnaire was used to measure function. [Note: The SF-36 is a health survey with only 36 questions. It measures functional health and well-being as well as physical and mental health. It is a generic measure, used to compare the relative burden of diseases, and to compare the benefits produced by a wide range of different treatments.]

Interestingly, the highest scores on the SF-36 were mental health and emotional role (activity limitations due to emotional problems). [Note: This calls into question the frequent assertion that depression is a common comorbid condition of CFS/ME. It also reveals one of the flaws of using a case definition for CFS/ME that does not exclude clinical depression.]

The lowest scores were vitality and physical role (activity limitations due to physical health)

In this group of patients, daily vertical activities (upright or sitting with feet on the floor) averaged 7.2 hrs and the exercise average was 3.4 times a week, which means this was not a severely ill population.

Measures of pain: 80% had pain last week

Symptom scores were very illuminating [timestamp 101.50]

The symptoms that were most often reported as most severe were fatigue after exertion, and unrefreshing sleep

Cognitive problems varied between those who had severe problems or none.

[Note: The distribution of symptoms is reflective of a patient population that is 1) older, and 2) has already passed the initial stage of the illness, in which flu-like symptoms predominate.]

Finally, Dr. Unger showed a chart that compared findings of the PROMIS scores for symptoms of CFS/ME against five other conditions: chronic pelvic pain, spinal cord injury, muscular dystrophy, post-polio syndrome, and MS. While sleep and pain that influences what you can do is about the same in chronic pelvic pain, in all the other measures: fatigue, sleep disturbance, pain, CFS/ME scored higher than the other conditions.

Conclusions: There is heterogeneity in the CFS population as a whole and measures based on symptoms alone are limited in their ability to determine subgroups. The CDC data will, however, allow the CDC to evaluate how well these instruments work.Fourth speaker: Dr. Ashley Slagle, “Clinical Outcome Assessments to Evaluate Treatment Benefit in Clinical Trials for CFS and ME.” [timestamp 108:24 – 138:39]Dr. Ashley’s main point was that in order to find effective therapies we must be able to assess those therapies in a reliable fashion. The FDA requires that drug developers provide documentation of “substantial evidence from adequate and well-controlled clinical trials” and that the methods of assessment of the subjects’ response be “well defined and reliable.” Well defined and reliable are the key criteria by which the FDA judges outcome assessments.

How the FDA measures treatment benefitBenefits are determined by how patients feel, function or survive. Clinical studies use biomarkers to determine the effectiveness of a medication, however, biomarkers do not tell us how a patient feels, functions or survives.

Biomarkers may, however, provide indirect evidence of treatment benefit, by showing a biologic treatment response to a drug. Because there are currently no agreed-upon biomarkers to use as outcome assessments for CFS/ME, it is critically important to find assessments that can tell us how patients are feeling or functioning.

To determine how patients feel and function, clinical outcome assessments (COA) may be provided by patients, clinicians or caregivers. Unlike biomarkers, COAs are influenced by patient choices, because they depend on reporting. They require rigorous development and evaluation. Assessments reported by patients can also be used for epidemiology, prognosis, and other contexts. COAs do not need to be used in conjunction with a biomarker – FDA says that any assessment can be defined as well reliable.

Another important consideration when measuring treatment benefit is the context of use. Context of use includes disease definition (which must be explicit and specific) as well as characteristics (severity of disease). What is important is that the assessment match the population in which it is being used, taking into consideration age, severity, comorbidities, etc.

Challenges to developing outcome assessments: Subpopulations

One of the biggest challenges in CFS/ME is that the disease definition is not entirely clear. Therefore, it is important to identify a rational set of clinical trial entry criteria which permit the exclusion of other comorbidities as much as possible.Another challenge is that subpopulations need to be defined. Some of these are:

Acute and gradual onset

Patients with OI and those without

Adults and children

Those with abnormal neurological findings and those without

Recent onset and those with long-time suffering

Severe forms and less severe forms

Patients with varying symptom experience

Others?

Defining subpopulations for clinical trials

There are already a number of existing instruments that can be used to measure the symptoms and domains of subpopulations of CFS and ME. But they have not been specifically developed for CFS and ME, so they may need to be modified to use for CFS and ME. (slide)Some concerns are that some instruments have been developed for diagnosis, or epidemiology, so they are not useful for clinical trials. Generic measures are not specific enough, and include items that are not relevant to the CFS/ME population. There are conceptual framework concerns, for example how is “fatigue” defined? Sometimes the measures do not include activity level, which is very important in CFS and ME.

In spite of all the hurdles of complying with FDA regulations for determining the efficacy of a treatment, Dr. Slagle closed on an optimistic note. While none of the assessment instruments have been appropriate for CFS and ME overall, there are other options: assessment instruments can be used for specific subgroups, modified, and new instruments can be developed. To ease this process and ensure their conformity to FDA regulations, modifications can be made by independent groups (including those other than drug companies) and submitted to the FDA for use in future trials through the Drug Development Tool (DDT) qualification program.

Question and Answer Period: [timestamp 138:52]Question: It’s clear that we need large clinical trials, because of the heterogeneity in the patient population, but those trials are usually paid for by pharma, which is not interested in funding large trials for CFS and ME. Patients do not have the resources to bridge this gap. Comments?Answer: Dr. Rowe: This is a big problem. If studies don’t come from pharma, I don’t know who would fund them. Dr. Snell: This is a major economic problem. Yes, we need something to drive it. Dr. Slagle: If you develop good outcome assessments for pharma to use and lower the risk, and if they have well-established measures they can use, in consultation with the FDA, they are more likely to engage in clinical studies. Ms. Unger: Once we get a critical mass of data, and infrastructure, pharma will come. CDC is making a start on the data. Dr. Kogelnik: One of the promising funding avenues is a shared grant mechanism through a partnership with the NIH.Question: Only 18% of patients with ME/CFS have those diagnoses exclusively, with no comorbidities. The high rate of comorbidity may be an additional challenge for clinical trials. Comments?Answer: Dr. Rowe: Fibromyalgia has a high rate of comorbidities, yet it has a number of approved drugs. A large enough sample size will randomize comorbidities. Another option is that while any two people have a lot of differences, each person can act as his or her own control.Question: Dr. Unger, infection/immunization is in your database. Have you made any connection between immunization and onset or relapse, and are the data maintained in such a way that such an analysis could be done?Answer: Dr. Unger: We don’t have onset correlated with infection or immunization. We will have that information when the data are analyzed. We think this will be an important data point.Question: Does the FDA assist with the development of trials and with developing outcome measures?Answer: Dr. Slagle: There are two processes for outcome assessments. During the course of normal meetings with drug developers, the FDA will respond. The other option is the independent qualification process (DDT program) in which the FDA will provide specific consultation. The FDA welcomes the opportunity to talk with those who are designing trials and endpoints; the earlier the better.Question: What does substantial improvement in VO2 max – and in steps walked – consist of (as per the Ampligen trial)?Answer: Dr. Snell: We don’t have a lot of data related to treatments, because we don’t know what is causing the deficit. If the immune system is causing the problem, then treating the immune deficit will show improvement. There are no criteria for steps. Counting steps is not necessarily helpful unless you decide to relate it to something else.Question: Is there insurance coverage for exercise testing?Answer: Usually, insurance reimburses.Questionfrom Dr. Grobstein to Dr. Unger: The FDA says the patient population must be well defined for clinical trials, yet the CDC study does not ask participant clinics to use any particular definition. How do you reconcile these two views of how to do trials?Answer: Dr. Unger: Ours is not a treatment trial. We are collecting data on what ME/CFS looks like in the clinic. That objective data can be used to develop a case definition. There are times when you want a broad case definition, and times when you want a narrow one.Questionfrom Dr. Grobstein to Dr. Slagle : You briefly pointed out problems with outcome measures – the instruments are not ideal. Does this mean we can’t do trials until we modify existing instruments or develop new ones.Answer: Dr. Slagle: Not having great instruments shouldn’t hold up progress on trials. The problem is that although there may be a treatment benefit that’s there, it may not be picked up by the instruments being used. On the other hand, if there is a huge treatment effect, then existing instruments will show it. Until existing instruments can be modified, mapping the instrument to the population, even if it isn’t ideal, is what is important.Question: What knowledge may be obtained by brain mapping, and what impact will that have on general research?Answer: Dr. Unger: A lot of data will be coming from brain studies, eventually.Question: What is the prevalence of CFS in different racial and ethnic groups? Answer: Dr. Unger: CFS is very common in racial and ethnic minorities.

Question 1: What were the key messages on drug development you heard in this meeting?Dr. Lily Chu: Data is necessary to do research. But not enough money is being spent on CFS research. Severely ill patients need to be studied.Dr. Dimitrakoff : The key message is that it is actually possible to have a drug for CFS. The second message is that there is a great deal of support from the FDA supporting the development for medications for CFS/ME. This meeting validates how important it is to get young people involved in CFS research in the early stages of their careers.Dr. Klimas: We are much further along than we think. Investigators are already linked together, and we have many years of experience using the instruments we’ve been talking about.Dr. Nancy Lee: Partnerships with academia, patients, clinicians, pharma, and foundations are necessary to bring these efforts to fruition.Dr. Susan Maier: Measurement is the key to making sure we have accurate representation of what happens in clinical trials and research.Robert Miller: There is a crisis in the ME/CFS community and that crisis is lack of treatment. Measurements already exist that can be used to evaluate CFS symptoms. The government needs to take action now to clarify a very clear special pathway to approval for drugs for ME/CFS. This will make it clear to pharma that FDA will support drug development. Fund it and they will come. Treatments must not be withheld because of the heterogeneous population. FDA should move within the next two months to create a set of criteria and outcome measurements. CDC and NIH should study the responders to Ampligen to find out for whom it works and why. This is a crisis, this is an emergency, this is a time for everyone to work together and try to move forward.Dr. Theresa Michele: Patients were articulate and clear.Jody L. Roth: It is essential for pharmaceutical companies to understand endpoints. We have the correct framework to continue forward.Question 2: What do you think are the most important factors in facilitating drug development in CFS and ME? [timestamp 29:21]Jody L. Roth: What are the criteria we need to have in place for clinical trials? What is the framework, how are we going to implement the trials to get the endpoints in place? How can we leverage other fatigue instruments we have used in order to find out if our drug will work in this syndrome?Dr. Theresa Michele: We have a need for data. We already have a lot of data, but we need more longitudinal data. There are a number of different databases already out there. We need to establish networks to bring those databases together.Robert Miller: Willingness from all the federal health agencies to work together and figure out the pathway to do clinical trials. A plan needs to be in place in order to move forward.Dr. Susan Maier: Be willing to accept researchers working on other diseases to broaden how we do research.Dr. Nancy Lee: Developing data infrastructure is very important. Drug repurposing has promise in the shorter term in order to find useful therapies that have already been approvedDr. Klimas: The most important facilitating factors have to do with organizational infrastructure. We have the platforms, and things are cheaper than they used to be. It is very reasonable to think about putting together a series of clinical trials. Subgroups of patients can be a strength, because it helps us target specific drugs and therapies. There is no reason, at this point, in delaying any further. We have good reliable, validated, well-published variables already. We’re ready to go.Dr. Dimitrakoff: The key word is collaboration. It is important to work together with people in similar and related fields.Dr. Lily Chu: A big piece of research is educating researchers and physicians about CFS/ME. 85% of physicians think that the illness is psychiatric. There are biomarkers for CFS/ME. [applause] What’s more CFS is not the only disease with a lot of heterogeneity or comorbidities. It is not a unique disease. Question 3: Based on the discussion from Panel 3, what clinical trial design elements are most important to ensure success of drug development programs for CFS and ME? [timestamp 43:42]Dr. Nancy Klimas: Important design elements are: sample size, symptoms that have to ability to improve and which you can measure, and the length of the trial itself. Little 10-week and 4-week trials may not be enough. You need at least four months to get even a hint of efficacy. Our group is using an exercise challenge to induce relapse, intervening with the targeted drug, and then challenging the system again. This not only demonstrates the efficacy of the drug, but it teaches us more about the dynamic of the illness.Dr. Michele: It is critical that we not forget measures of safety. Efficacy is only half the equation. So we need to understand clearly what the risks are, even for drugs that are being repurposed.Dr. Lily Chu: There are two papers which might be interesting to pharmaceutical companies. One is by Haywood, “Quality and acceptability of patient-reported outcome measures used in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review.” [Read the abstract HERE.] The other paper is by Cockshell, “Test effort in persons with Chronic Fatigue Syndrome when assessed using the Validity Indicator Profile.” [Read the abstract HERE.] Question 4: What do you think are the most important barriers to conducting research for CFS and ME, and what can be done to overcome them? [timestamp 47:36]Dr. Michele: From the FDA ‘s perspective, we don’t perceive any barriers. We have outcome measures, we have definitions, we have symptoms that can be used. Regulatory-wise we are ready to go.Dr. Chowdhury: The time has already arrived to enroll patients in trials.Dr. Dimitrakoff: There are two barriers that have been consistently pointed out: lack of new investigators coming into the field, and limited availability of funds. All the clinical centers should come together and do a large clinical trial. The NIH has something called the U34 grant, which allows teams of investigators to come together to design a clinical trial over a period of one or two years. Following that period, there is an additional funding period of five years when you actually do the trial.Dr. Maier: Money is the primary obstacle. What drives funding from the NIH is well-conceived ideas, good science and well-written proposals. We can’t fund research, even requests for applications, without a proposal. [Submit them and they will come.]Question 5: How can we best leverage your individual experiences in order to facilitate drug development in CFS and ME? Please respond for your group (Health and Human Services, FDA, pharma, academia, patient/advocacy).Dr. Michele: FDA can express its willingness to work with companies and investigators on drugs for CFS. If FDA considers CFS to be a serious disease, this sends a message to pharma that this may be a good opportunity to make some money. Money makes the world go round. When people come in with clinical trials, we can help them with trial design, and with lessons learned from other diseases. Our division has its doors wide open for applications for CFS.Dr. Maier: Call me. [This was a direct personal invitation to researchers to seek advice and recommendations on proposals from Dr. Maier.]Jody L. Roth: Pharma needs to get together with these consortia to establish endpoints and measurements that we can use.Dr. Lee: We need data infrastructure, and the CDC is doing that.Bob Miller asks Dr. Klimas to talk about her applications.Dr. Klimas: We write eight applications for every grant that we get. From the point of view of academia, we need philanthropic support. You want us to be quicker, so that you can have your drugs, but I am struggling to get Phase I work done. It’s not that we don’t have good ideas, or good science. What we don’t have is your time to waste. Dr. Klimas stated that she has nine grants on the board right now.Dr. Chu: IACFS can help disseminate information. Patient groups are enthusiastic to work with anyone. NAAME is a patient organization that will help facilitate this. http://naame.org/Question 6: What are possible next steps following this meeting? (Please respond as per your group.)Dr. Klimas: We need to have a small meeting with the experts in the FDA to talk about outcome variables, and really nail them. Dr. Klimas volunteered to come back to Washington DC to do that. (Dr. Dimitrakoff did as well.)Jody Roth: we need regulatory effort for trials to move this forward.Dr. Michele: Guidance for industry is the next step. This will not happen quickly, but we are very well aware that it needs to happen.Dr. Dimitrakoff suggested that a peer-reviewed paper should come out about the FDA meetings, so that the larger medical community has some idea that the field is moving forward. [applause]Dr. Chu: Publishing in a peer-reviewed journal is also a way to engage new researchers.Question and Answer Session [timestamp 74:10]Questions: Are there clinical FDA trials approved for CFS? Why was Ampligen not approved? Does FDA have a working group to write industry guidelines?

Answers: First question: There are approved clinical trials, but not too many. Second question: FDA sends a response letter to the drug company and that is confidential. [Third question not answered.]Question: Bob Miller: What are the approved clinical trials?

Answer: Dr. Michele: Just google CFSAC.Question: How can repurposing of drugs be financially worthwhile for a pharmaceutical company?Answer: Jody Roth: We are look for line extensions, or new uses, to add to existing drugs.

Question: Is anybody lobbying Congress to set aside money for CFS research?

Answer: Lily Chu and Bob Miller said they were both lobbying, but they did not have sufficient energy to do so.Question: How are serious adverse events taken into account, especially in light of the fact that any hospitalization is considered a serious adverse event, whether it is drug-related or not.Answer: Dr. Michele: This is why we need large groups for clinical trials. Serious adverse events can then be measured in both treated and non-treated groups.

Question: We have biomarkers, so why does the FDA continue to insist that we have none? What needs to be done to validate NK cell function, immune markers, and viral titers as biomarkers?

Answer: Dr. Chowdhury: Biomarkers are not needed for clinical trials. There is no up-front need to develop a biomarker. Dr. Klimas: The primary outcome needs to be function. What we need is something to predict function, and, yes, I do think we have the data to support that we have biomarkers that predict function. Both Dr. Chu and Jody Roth pointed out that biomarkers are indeed necessary for establishing subgroups and outcomes.

Day Two (April 26, 2013) of the FDA’s Drug development workshop for ME/CFS focused on clinical trial design, outcome measures, regulatory issues and possible pathways to expedite drug development for CFS and ME. The purpose was not to discuss individual products, but to discuss how to get effective drugs through the pipeline quickly.

Note: For additional coverage of the second day read Cort Johnson’s article on HealthRising.

You can read a summary of the presentations made on April 25, the first day of the workshop, HERE.

You can read a summary of the afternoon April 26th sessions HERE.Welcome by Dr. Michele: Objectives of Day 2: To examine common issues in drug development, and consider scientific and regulatory tools that might be brought to bear to move drug development forward in this area.(15:29) (VIDEO)Panel 1: Drug Development, Innovation, Expedited Pathways, Regulatory Considerations (96:21) (VIDEO)Panelists: Dr. Bernard Munos, founder of InnoThink Center for Research and Biomedical Innovation, Dr. Suzanne Vernon, scientific director of the CFIDS Association of America, Melissa Robb, associate director for Regulatory Affairs at the Office of Medical Policy.

I. Presentations

First speaker: Dr. Bernard Munos [timestamp 4:59 - 31:26]Dr. Bernard Munos spoke on “Drug Innovation and Derisking Drug Discovery.” [Note: “Derisking” in this context does not mean lowering the risk to patients taking drugs, but making drug discovery attractive to pharmaceutical companies.] The question Munos asked was, “How do we get innovation in CFS and why don’t we have innovation like we do in HIV and a number of other fields.”

Summary: The traditional model for drug innovation is not suited to a complex illness like CFS. Drug hunters generally look for established illness that new products can be developed for. There is a dearth of discoveries that could be turned into novel drugs for CFS. There is also lack of infrastructure, namely, data and tools. The disease shares symptoms with many other illnesses, therefore treatments address symptoms, not the underlying cause. The lack of a single etiology, and the shared symptoms makes for an ill-defined situation, which makes it hard for regulators to do their job. What is needed is an innovation supply chain. Patients have to make it worthwhile for scientists to investigate the illness.

How do we make it worthwhile?

1) We need data. There cannot be science without data. Data drives innovation. The data challenge in CFS/ME is magnified by its heterogeneity, which means we need more patient data. We also need international data to understand how CFS/ME affects people who come from different backgrounds. The natural history of the disease needs to be better documented, and genomic data must also be collected. Patients are the only ones who are qualified to speak on this.

2) We also need tools – tissue banks, animal models, biomarkers, and networking tools. The ability of scientists to “cross pollinate” across international boundaries is essential. Although patents are competitive, data are not, which means we should collaborate on the science. If you create the tools, the scientists will come.

3) Partners are essential for drug innovation. Partners include established scientific leaders, physicians, and young investigators. CFS/ME is a virgin field, which means it is important to attract young, enthusiastic researchers. Because they are on the front line, physicians should also be involved. Historically, physicians have been the most powerful source of innovation, because they know about the illness, and they customize and experiment with drugs that are used for other conditions.

4) Passion raises quality and success. Parents who have children who are ill, for example, agitate and become specialists in the disease. Scientists are moved by the passion of these parents, who are driven to find cures. Passion also lowers costs and raises the possibility of success. It’s hard to say "no" to people who are driven to a level of passion, and for whom failure is not an option.

5) Money is not as much of an issue as people think. You can run a very audacious program on a shoestring. Waste is prevalent in this industry – but it’s getting cheaper to gather data. The CFS/ME community is larger than other communities, so the ability to raise money is already there. Gathering data can be done cheaply, if it is taken up by the patient community.

When you have all five of those ingredients, you get to the point where you can generate intellectual property. At that point you can get companies interested in developing new drugs for CFS/ME. Munos' message was: “Frankly, for industry, CFS hardly exists … but if you build it, they will come.”

Second speaker: Dr. Suzanne Vernon [timestamp 31:36 - 60:42]

Dr. Suzanne Vernon, scientific director of the CFIDS Association of America (CAA), gave a presentation entitled, “Knowledge and Intuition to Reposition Drugs for CFS.” The subject of the talk was drug repurposing, or the use of existing drugs to treat CFS/ME. Dr. Vernon also spoke about “derisking science” i.e. making the research on CFS/ME attractive for industry, and for pharma.

Summary: The CFIDS Association of America is currently finding ways to make information that comes from the bedside available, and attractive, to the pharmaceutical industry. The Association is gathering data through their Solve CFS BioBank, which includes a repository and registry. There is already a tremendous amount of information about CFS. There are over 6,000 abstracts and articles in PubMed about CFS/ME. Dr. Vernon stressed that we do, in fact, understand the pathophysiology of the illness. We simply lack validated markers for replication and we have no standardized guidelines or a regulatory framework. Because of that, our doctors are still treating CFS/ME symptomatically, which has both advantages and disadvantages. The advantage of symptomatic treatment is that because its symptoms are so numerous, CFS/ME is ideal for drug repurposing.The CFIDS Association has partnered with BioVista to mine information in PubMed and other databases through a search engine called a Clinical Outcomes Search Space (COSS). COSS searched through 20 million abstracts on PubMed, combined with a “whole bunch” of databases, which they then queried to extract information about CFS/ME. This technique can be used not only to identify drugs, but to identify biomarkers. The outcome is an extensive amount of data that people can then hone down to a plausible list that correlates symptoms and markers with medications.

[Dr. Vernon showed a number of slides which, unfortunately, were almost impossible to read.]

The most prominent association that COSS found was with serotonin, which was highly correlated with symptoms. From this data, Dr. Vernon drew the conclusion that some of the drugs [antidepressants] being used in this population may be contributing to symptoms. A second database measuring adverse events also indicated that the frequency of exhaustion was very high with antidepressants. These findings validated the central fatigue hypothesis of CFS, i.e. CFS fatigue is generated in the central nervous system.

Using the COSS, two drugs were identified which, in combination, might address sleep, pain and fatigue. [Regrettably, Dr. Vernon could not tell us which drugs those were, as they are currently under investigation.] Vitamin B12 injections were identified as effective in treating brain fog.Dr. Vernon went on to talk about the results of the patient survey conducted by the CAA. Responses from the association’s survey showed symptoms clusters that could group patients into phenotypes. She noted that the pain subgroup was very distinct from the others. In terms of treatment, most patients used supplements and complementary strategies as well as anti-inflammatory drugs. The lesson learned from the survey is that patients have a lot of information that cannot not be discovered except by asking them directly.

Dr. Vernon finished her presentation with three proposed steps to help further research: taking the next steps in drug repurposing by expanding the Biobank, optimizing clinical information from physicians, and operationalizing data collection from patients.

Third speaker: Melissa Robb [timestamp 61:16 - 78:23]Melissa Robb, Associate Director for Regulatory Affairs at the Office of Medical Policy at FDA gave a talk entitled “Drug Development and Review: FDA’s expedited Programs for Serious Conditions.”

Ms. Robb spoke about the history of the FDA’s expedited programs for serious conditions and explained the FDA’s rules and regulations that pertain to this area. She defined two common terms that are common in expedited programs:

Serious conditions are associated with morbidity that has a substantial impact on day-to-day activity, including life-threatening conditions.

Areas of unmet medical need are illnesses that have no approved therapies, but also those conditions in which new drugs may show an advantage over available therapy, if one exists.

There are four expedited drug approval programs:

1) Fast track designation - is determined by whether there is data (clinical and nonclinical) to address an unmet need. It allows sponsors to complete portions of applications, rather than submit a finished package. This is called a “rolling review.” The goal is to speed up the development process.2) Breakthrough therapy designation – addresses the development of drugs for serious conditions. It covers all aspects of development, review and production. Like fast track, this helps developers.

3) Accelerated approval – uses an endpoint that is clinical, and can be measured earlier. Allows FDA to take into account a lack of availability of appropriate therapies. The endpoint is likely to show a benefit, but there is safety and efficacy to consider as well. These clinical endpoints shorten the approval process. The accelerated approval program has been used extensively with cancer and HIV. Post-market validation is required.4) Priority Review – a program that is intended to shorten review time (by the FDA). Typically the review time is 10 months. For a priority review, the period is 6 months. The drugs that qualify must have the potential to provide a significant improvement in safety or effectiveness.

Question and Answer Period: [timestamp 81:35]Question: From Dr. Vernon to Bernard Munos: As far as drug development in concerned, what kind of time frame would you put us on?

Answer: Under normal circumstances, it could take 10 to 15 years to get a new drug on the market. But this period can be shortened by half, if patients get involved. Dr. Munos stressed the point that with a million people with CFS, patient involvement is key, and could contribute significantly to getting new treatments developed and approved. We need more networking between physicians, scientists and patients to accomplish this goal. There must be a rich network of ideas and hypothesis for physicians to draw upon.

Question: Dr. Vernon, you searched only for fatigue and exhaustion in adverse event database, so it’s not surprising that you came up with neurotransmitters. Have you looked at multiple infections, orthostatic intolerance, and abnormal immune functions? It seems to me you are biasing your results by your choice of search terms.

Answer: [Dr. Vernon could not answer the question, facing the panel instead and asking, “Can you guys help me out on that?”] Yes, there probably is some bias. But the result was clear that fatigue was associated with the mechanism of these drugs.Question: Dr. Vernon, are the results of the survey available online?

Answer: Yes. Well, not yet. We are still collecting data.

Question: Dr. Vernon, it is known that the “CFS” literature includes studies based on overall broad and non-specific definitions. As a result, these studies don’t have the disease that patients described yesterday. Did you eliminate those studies from the Biovista analysis, and, if not, how has that influenced your results? Answer: The 20 million PubMed articles were not culled. The search was based on terms used to describe CFS. It’s an agnostic approach. We tried to be as inclusive as possible. Dr. Kweder: This is a heterogeneous group.

Question: Ms. Robb, is low-grade fever a surrogate marker?

Answer: [Ms. Robb was not comfortable answering the question.] Dr. Kweder interjected with, “That depends.” What is low-grade fever a surrogate marker for? In AIDS it predicts mortality. But the companies were required to show that low-grade fever actually led to mortality once they were further down the road. The key is that you have to show that the marker is predictive after approval.

II. Panel 2: Symptoms and Treatments: A View from Clinicians and Patients (71:37) (VIDEO)Moderators: Nancy Klimas, M.D., FACP, FIDSA, Chair, Department of Clinical Immunology, Director, Institute for Neuro-Immune Medicine, Nova Southeastern University and Theresa Michele, M.D., Clinical Team Leader, Division of Pulmonary, Allergy, and Rheumatology Products (DPARP), Office of Drug Evaluation II (ODE II), Office of New Drugs, CDER, FDAPanelists: Lucinda Bateman, M.D., Fatigue Consultation Clinic, Salt Lake City, Utah, Lisa W. Corbin, M.D., FACP, Associate Professor, Division of General Internal Medicine University of Colorado Denver School of Medicine, Lily Chu, M.D., MSPH, International Association for CFS/ME and Patient, Jose G. Montoya, M.D., FACP, FIDSA, Professor of Medicine, Division of Infectious Diseases and Geographic Medicine Stanford University School of Medicine. Jennifer Spotila, JD, Patient and Christine Williams, MEd, Patient.Questions: What were your key take-away messages from the discussion yesterday on the most significant symptoms experienced by patients with CFS and ME? Please describe any significant differences in your experience as clinicians and patients compared to yesterday’s discussion. [timestamp 8:44 – 24:00]Dr. Bateman said that she concurred with what she heard yesterday. She would add the psychological suffering that comes along with the illness. Top of the list are cognitive limitations and fear.Dr. Lily Chu talked about the results of the survey she conducted. Fatigue, PEM (post-exertional malaise), pain, and cognitive impairments came first. Multiple chemical sensitivities, gastro-intestinal symptoms, and orthostatic intolerance appeared in over 50% of respondents. The impact of the illness was substantial: respondents were more than 95% impaired and 89% needed assistance for daily chores.Dr. Montoya stated that the two most salient clinical features were cognitive dysfunction and unpredictable crashes. The ability to drive is significantly impaired in his patients. This makes sense, because driving is the perfect example of multi-tasking. When patients get better they start to come to their visits alone. Herpes simplex is a trigger in a cohort of patients. The third thing to consider is that there are several triggers for patients. We should keep in mind how the effect of a drug is undermined when there are several triggers.

Christine Williams, who became ill at the age of 56, brought up the “double whammy.” These are the effects of this illness on an aging population. For her, the flu-like symptoms are the worst, because they make her feel very sick.Jennie Spotila: We need to remember that the working ill, who struggle to maintain jobs and raise families, are a significant part of the patient community. For her, the words “fatigue” and “tired” are placeholders to avoid the long description of a crash. She stressed the need to include multiple aspects of cognitive function in order to measure improvement in drug trials. Ms. Spotila noted that gut disturbances had not been addressed. She also pointed out that prevalent symptoms, like orthostatic intolerance, can be masked. In addition, many symptoms could be measured and identified, but people are not looking at them. There is a lot of suffering that is going under the radar.Question 2: Based on your expertise as clinicians and your experience as patients, which symptoms of CFS and ME could be identified as valid, quantifiable and reliable outcome measures or endpoints in clinical trials to evaluate potential drugs to treat CFS and ME? [timestamp 24:01 - 39:10]Dr. Lily Chu: Any symptom of ME could be used as a valid and quantifiable outcome measure, it depends on which scales you want to use and which drug you want to test. She also mentioned that because the disease is heterogeneous, studying subgroups would yield better results. Her second point is that it is very important to come up with a good outcome measure for post-exertional malaise. Post-exertional malaise (PEM) is not that same as post-exertional fatigue. Malaise can have a flu-like component, and involves collapse and confusion. There is not enough basic research on PEM. The difference between fatigue and fatigability is important, because it not only takes into account the subjective feeling of feeling tired, but puts it in relation to activities. The real test is whether a drug improves function, rather than measuring a subjective state.

Dr. Montoya talked about the importance of separating out symptoms. He mentioned a double-blind study he did in whicha smallgroup of patients were given antivirals. Their cognitive symptoms improved before their physical symptoms, but this improvement was only discovered when they compared a subscore on their initial questionnaire. Otherwise, it may have been missed. Separating cognitive fatigue from physical fatigue could be helpful for clinical trials. Because of the fluctuating nature of the disease he recommended using linear regression statistical models in order to measure various points, rather than simply comparing a beginning and endpoint. Type of onset is also extremely important. Do patients have viral onset, abrupt onset? What is the duration of the illness? “It’s very hard to believe that a patient with CFS of two years’ duration would have the same pathogenesis as a patient with 20 years’ duration”.Dr. Lisa Corbin brought up the point that while it is important to look at function as an endpoint, there may be different parameters for function in the CFS/ME population. For example, being able to read a book for two hours (or at all) will not appear on any functional scale. The way we measure function needs to be more specific for this population. It’s important to follow the symptoms that are most distressing for patients.Dr. Bateman mentioned that there are already objective measures in place to measure orthostatic intolerance, sleep disorder, as well as other symptoms. One problem in clinical testing is that as a patient’s ability to function increases they do more, which produces symptoms. So, unless patients maintain the same level of activity throughout the trial, measuring symptoms is unreliable.III. Question 3: What are the key factors you take into account when making decisions to prescribe (as clinicians) or use (as patients) therapies to treat symptoms associated with CFS and ME? [timestamp 40:00 - 56:15]Dr. Lisa Corbin: The first factor is patient input. I treat the most disabling symptom first. I do treatments one at a time. Start low and go slow.Dr. Bateman talked about individualizing treatments as well as managing and coping strategies.

Dr. Montoya talked about preventing the wild fluctuations of the illness. He also addressed treating infectious triggers. He does PCR tests for HHV6 and measures viral loads. Those patients are treated separately. Other patients undergo testing to identify other viral triggers, risk factors for Q fever, and other pathogens. But, Dr. Montoya stressed, the pathogens must be correctly identified.Question 4: If you had a drug to explore what would be your top one or two choices? [timestamp 56:26 – 58:56]

Dr. Bateman: On top would be antiviral and immune-modulating drugs. Next would be symptom management drugs for pain, stimulants for cognition, and sleep meds and meds for OI (orthostatic intolerance).

Dr. Lily Chu: Same plus Rifaxamin

Dr. Montoya: Antivirals, immune modulators. He believes that the immune response to the infectious agent is what drives CFS/ME symptoms, but for some patients it may be too late.

Jennie Spotila added Rituximab, as well as drugs that can increase VO2 max. These could potentially make a huge difference in the functionality of patients.

Question and Answer Period [timestamp 58: 56]Question: How do we deal with the fact that so many patients are not located close to clinical trials?Answer: Dr. Klimas mentioned that there is a spouse CBT protocol that involves long-distance CBT via a video group session. (Dr. Klimas noted that CBT is not a treatment.) Dr. Klimas added that there is a disconnect between 20-year-old guidelines and how doctors actually treat their patients.[Questions about viral makers and immune markers were referred to, but the questions were not read.]Questionfor Dr. Montoya: “Do you subgroup out to foreign diseases, and what is the prevalence of HSV and CMV in your practice, and do you use cidofovir (Vistide) for HSV positive patients?Answer: Dr. Montoya: We have a small group of patients with positive test results, but it is hard to come up with treatments for tick-borne illnesses. For herpes simplex we use acyclovir. We reserve cidofovir for patients who are severely ill, because it is very toxic. Doctors need to remember to “do no harm.”Question: How can we better break down the barriers of data sharing?

Answer: Lily Chu: There are problems with privacy when it comes to freely disseminating medical data from individual patients. Dr. Montoya: Something similar needs to be done as was done for AIDS. Within 15 years they had highly effective treatments. We need a “bailout” for CFS/ME, a huge infusion of money and infrastructure. Dr. Vernon mentioned that CAA requires that anyone they give a grant to must share their data. Dr. Klimas stated that NOVA shares its data with other CFS/ME institutions, and there are other multi-institutional initiatives underway. Dr. Montoya mentioned that Stanford also has a biobank of several hundred CFS/ME patients. There is, in fact, a large amount of data already gathered and accessible for pharmaceutical companies.Originally posted on ProHealth.

On May12th - International CFS/ME and FM Awareness Day - members of the ME/CFS community sent a letter to the Department of Health and Human Services asking for a change. They wanted the vague, out-of-date definition of CFS to be changed to the more accurate Canadian Consensus Criteria for ME (myalgic encephalomyelitis). Theirs was a reasonable, well-argued letter, with all the facts, and with all the logic that a long-suffering population could bring to bear.

The current definition is simply too broad, the letter said, and confuses CFS/ME with “fatigue,” thus lumping people with ME together with people with depression and simple deconditioning. The consequence is that, left untreated year after year, comorbidities develop, and people with ME may end up dying from premature heart failure, cancer, and suicide. They also die of ME. In 2005 Sophie Mirza became the first person in Great Britain to officially die of chronic fatigue syndrome.The DHHS ignored the request. They ignored Sophie Mirza.They also ignored Sophie Coldwell.

In March 2013, 17-year-old Sophie Coldwell was diagnosed with CFS. Ten days later she was dead. The cause of her death was leukemia. But she hadn’t been diagnosed with leukemia, she’d been diagnosed with CFS, because she was tired. Is Sophie an aberration, someone who somehow “slipped between the cracks”?She is not.

In the U.S. over 30% of existing MS patients – that’s 1,584 people - were diagnosed with CFS before being correctly diagnosed with MS. These are people who, had they been properly diagnosed in the early stages of the illness, would have had access to treatments that might have slowed or even halted the progression of the disease. Instead, they were told they had “chronic fatigue syndrome,” an illness for which there is no treatment. Those 1,584 people have now had their diagnoses corrected to MS. Just imagine how many people with MS are currently being diagnosed with CFS.But it doesn't end with hard-to-diagnose illnesses.More than 10% of people coming to “fatigue centers” in Belgium have been found to have physiological injuries to their pituitary glands – cysts, tumors, and a shrunken pituitary (empty sella). They had been diagnosed with CFS because they were tired. And because they had CFS, nobody bothered to do an MRI of their brains. Is this gross oversight limited to Belgium? It is not. I personally know one man here in the U.S. who, in fact, had no pituitary due to empty sella. It was years before a doctor thought of doing an MRI, because this man had been diagnosed with CFS.How many more people have to suffer – those of us with ME, those of us with cancer, Hashimoto’s disease, leukemia, MS – simply because the ridiculous diagnosis of “chronic fatigue syndrome” exists?This needs to stop. Now.Sign this petition. Tweet it. Facebook it. Reddit it. Send it to your family, friends, neighbors, co-workers. Let's put an end to this medical malarkey. We have 30 days to gather 25,000 signatures. And with everybody's help, we can do it.Do it for yourself. Do it for me.

The CFS/ME community has posed a number of questions concerning the petition to replace the CDC ("Fukuda") criteria with the Canadian Consensus Criteria for ME. The petition calls for dropping the name CFS entirely, replacing it with ME (myalgic encephalomyelitis), the term currently in use in the rest of the world. In this Q&A, Mary Dimmock, one of the founders of the newly formed organization, National Advocacy Alliance for ME (NAAME) answers frequently asked questions.

Question: What will happen to the patients who have been diagnosed with CFS? We cannot abandon the patients who have been given a “CFS” diagnosis incorrectly.

Answer: Patients with “CFS” will not be abandoned. It is critical that implementation of this change be carefully managed so that these patients are re-evaluated and given a correct diagnosis. If unexplained conditions remain, it will be necessary to perform the studies needed to understand these conditions and establish more appropriate names and definitions.

Question: How will this affect disability or insurance? We cannot afford to lose either one.

Answer: It will be important to have a carefully thought out implementation plan that manages this change to ensure that patients do not lose disability or insurance benefits simply as a result of changing the diagnosis.

Question: The vast majority of the 6000 articles in the literature use the name “CFS,” not “ME. If we stop using the name “CFS,” will we lose all that literature?

Answer: Researchers and professionals routinely learn about the history of names and definitions associated with any disease. They also need to understand what criteria were used in the past for any study under review.

This is especially critical with the “CFS” literature, because while it contains good research studying the essential features of ME, it also contains studies that used patients who met other conditions (i.e. depression and deconditioning) falling under the Oxford and Fukuda (CDC) case definitions. As a result, much of the “CFS” data does not represent one illness or even one illness with subsets, but rather a variety of “fatiguing conditions,” which have been thrown into the CFS diagnosis-of-exclusion wastebasket.

Continuing to use the “CFS” label will only exacerbate a very confusing situation, doing a disservice to ME patients and to all patients who deserve to be properly diagnosed and treated.

Question: We have more important issues to deal with such as funding, and attracting new doctors and researchers. Isn’t this just a side issue?

Answer: It is critical that we have more funding, but if we don’t fix the definition first, we will continue to study the wrong disease and have progress impeded by poor cohorts. The resulting confusion will make it difficult to attract young researchers and doctors who will not see a career opportunity in “CFS.”

Question: Research centers for CFS have recently been established. If we stop using the name “CFS” won’t that confuse the donors?

Answer: It is true that a number of research institutes have recently been opened and some of them use the term “”CFS” or even “CF.” But the donors to these institutes have a personal connection to the disease. They will continue to fund the centers no matter what the illness is called. However, attracting additional funders will be hindered by the confusion generated by the definition of the disease. The sooner we can resolve this problem, the better off we’ll be.

Question: CFS biobanks have been established using the Fukuda criteria. Will we lose those samples if the definition is changed?

Answer: The biobanks using the Fukuda definition could contain a mix of patients with ME and those who don’t. Using these mixed samples will continue to confound research. It is important that we have a well-characterized set of samples in the biobank and know which samples are from ME patients.

Question: ME may not be the right name. Shouldn’t we wait for science to figure out what the right name is?

Answer: It is possible that with further study we will eventually determine a better name. But because ME was adopted by the World Health Organization in 1969, it is the best placeholder until that time and avoids the serious problems caused by the use of the term “CFS”.

Question: Wouldn’t the best course be to tighten up the “CFS” definition, not get rid of it? Then we can keep the literature base, the biobanks, and so on.

Answer: There are two problems with this approach. First is the long history of the term “CFS,” which is non-specific and now widely associated with diverse conditions, especially psychiatric illnesses. This has tainted the term and made it clinically meaningless. Second, the term “CFS” is used for those studying patients who meet the Oxford criteria (which is essentially fatigue). As long as we keep the term “CFS” the Oxford criteria will remain in effect.

Question: Dr. Leonard Jason recently published a paper that reports that the ME-ICC and the Canadian Consensus Criteria include more psychiatric co-morbidities than the Fukuda definition, and recommended that more study be done. Does that mean we should wait to recommend any criteria until then?

Answer: Dr. Jason acknowledged that his study was limited due to the use of a questionnaire designed for the Fukuda definition. Additionally, the study was unable to assess one of the key ME-ICC symptoms because the data were not available. Finally, the study did not look at homebound or bedbound patients.

What is also significant in Dr. Jason’s study is that ME-ICC identified a much tighter group of patients (39 compared to 113 for Fukuda) with more functional impairments and physical, mental and cognitive problems than those meeting the Fukuda criteria.

Clearly, additional study is needed to operationalize the definition and to improve how it characterizes the disease, especially subtypes. But continuing to use the 19-year-old Fukuda definition - which is also not operationalized and does not describe subtypes - is not going to advance scientific knowledge and will only continue to hurt patients.

The Canadian Consensus Criteria (CCC) has been used clinically and in research for over ten years. There is no doubt that it better represents the disease. Using the CCC now will allow us to begin to make progress in research and to address the widespread dismissive attitude held by the medical community.

Question: We still don’t know for sure that post-exertional malaise (PEM) is real and we don’t have agreement on how to measure it. How can PEM be used by researchers as a primary symptom?

Answer: The work of Dr. Christopher Snell as well as the work of the Lights have not only demonstrated the reality of PEM but have provided the objective test to demonstrate it using the two- day cardiopulmonary exercise test (CPET). This test is the gold standard for functional capacity evaluations and is approved by a number of major American medical societies and organizations.

Question: Why were the Canadian Consensus Criteria and not the ME-International Consensus Criteria used as the initial baseline?

Answer: The Canadian Consensus Criteria has been used clinically and in a number of studies, providing the experiential foundation for its use. It is expected that as additional data is obtained, this definition will evolve. This must be done in partnership with the experts who developed the ME-International Consensus Criteria and the Canadian Consensus Criteria.

Question: Isn’t the Canadian Consensus Criteria is too complicated for doctors to use?

Answer: At the May, 2013 CFS Advisory Committee meeting (CFSAC), Dr. Unger raised a concern that the Canadian Consensus Criteria is too complicated for doctors. But we must not lose sight of the fact that this is a complicated disease and simple criteria, especially those like Fukuda and Oxford, that fail to require the hallmark symptoms of the disease are misleading doctors and hurting patients every day. Any doctor capable of treating the complexity of this disease will be able to understand the Canadian Consensus Criteria.

This is a letter written by Mary Dimmock, whose son has ME, to the entire CFS/ME community. Mary has been a steady ME advocate, testifying at FDA and CFS Advisory Committee meetings, and, most recently, helping to form the National Advocacy Alliance for ME (NAAME). In this letter she provides some background information for the recent DHHS letter sent by several ME/CFS organizations and advocates. Specifically, she answers the question: Why change the name?

There shouldn't be any doubt in anyone's mind that chronic fatigue syndrome, as a name and as a diagnosis, has to be dropped. Let's do that now. Sign the petition.

Dear Patients, Caregivers and Advocates

Of all the issues that we face today, the one which has created the most problems is the use of multiple, diverse, and overly broad “CFS” definitions. This single issue has severely affected research, drug development and clinical care and has misled the medical community on the very nature of this devastating disease, causing many doctors to dismiss their patients’ suffering. Until we stop this confusion over the nature of the disease, patients will continue to pay a terrible price.

Today, the CDC states that “chronic fatigue syndrome” can be described by any of a set of diverse definitions. Some, like the Canadian Consensus Criteria and the ME International Consensus Criteria, require the hallmark symptom of post-exertional malaise (PEM) as well as neurological and immunological impairment. But the two most commonly used definitions, the Fukuda (also known as CDC) and Oxford criteria, do not require this hallmark symptom. In fact, the Oxford definition only requires six months of disabling fatigue and allows primary psychiatric disorders.

The result? Myalgic encephalomyelitis, the disease seen in outbreaks throughout the twentieth century and recognized by the World Health Organization in 1969, has disappeared. In its place, we have the catchall term “CFS”, which has been associated in the literature with depression, deconditioning, medically unexplained chronic fatigue, and, for some researchers and clinicians, fatigue due to “excessive rest” or “false illness beliefs.” In clinical practice, the diagnosis of “CFS” is given to a variety of patients – those with ME, those with the conditions listed above, and those who have been misdiagnosed or whose doctors use “CFS” as a catchall for unexplained fatigue.

Exactly what disease are we talking about here?

As Dr. Carruthers stated in the ME International Consensus Criteria, “Research on other fatiguing illnesses, such as cancer and multiple sclerosis, is done on patients who have those diseases. There is a current, urgent need for ME research using patients who actually have ME.” We must have a disease appropriate definition for ME that is separate and distinct from all the other unrelated conditions encompassed by the overly broad, fatigue-focused “CFS” definitions.

To that end, a group of patient organizations and advocates have submitted the letter at this link (http://bit.ly/18hDBE4) asking the Department of Health and Human Services (DHHS) to adopt the Canadian Consensus Criteria, to stop using the term “CFS” and the non-specific definitions like Oxford and Fukuda, and to fully engage ME patients and experts in the planning and execution of this transition.

You may ask whether we really know enough about the disease or whether we need more study before we change definitions. Certainly, with more study, we can better operationalize the definition and validate biomarkers to make patient diagnostics easier. And we must get rid of the six-month waiting period. But in the meantime, we know that PEM is a hallmark symptom that reflects a distinctive biological pathology. We must use a definition that includes this pathway, and stop using the Fukuda criteria, which does not.Some of you may prefer the ME International Consensus Criteria over the Canadian Consensus Criteria.

The ME-ICC has some excellent features. But practically speaking, the Canadian Consensus Criteria has been used clinically and in research for a decade. Studies have been successfully completed using the Canadian criteria. The U.S. government has posted the IACFS/ME Primer, which is based on the Canadian Consensus Criteria, on DHHS’ Guidelines.Gov.

Changing the definition is going to be difficult, but adopting the Canadian case definition is more likely to be acceptable to the DHHS as a reasonable first step, especially when considered against the alternative of continuing to use the inadequate Fukuda criteria while more studies are done.

What about dropping the name “CFS”? You may be concerned that this means we will lose the literature base that has provided insights into the pathology of ME. Admittedly, some of the best articles have used the term “CFS.” And so have some of the worst. The point is that the literature base is a mess because the same label, “CFS,” has been used for multiple unrelated definitions for many years. When the term “CFS” is employed as the only label for so many different conditions, it loses all meaning. We need to stop using it.

Finally, what about the name ME? Does it really describe the disease? Is there a better name? That is a question that science will need to decide over time, but it is something that has happened in many other diseases which have changed their names as more information about them comes to light. What is clear is that “chronic fatigue syndrome” will never be an appropriate name for this illness, and should never have been established as a synonym for ME.

Patients have paid dearly with lost lives for the CDC’s failure to address definitional issues for the last thirty years. We cannot wait for more study to finally stop the harm being done to patients by the continued use of these overly broad definitions.

This problem must be addressed now.

You can help. Please sign the petition calling on DHHS to stop the confusion and start using the Canadian Consensus Criteria as a disease appropriate definition for ME.

This ground-breaking letter was sent to members of the United States Department of Health and Human Services on May 12th by the newly formed National Advocacy Alliance for ME/CFS (NAAME). You can support this letter by signing NAAME's petition. Change the definition - change the name!The full letter with Table 1 can be read at Onward Through the Fog.

Subject: Need for Focused Attention on Myalgic Encephalomyelitis (ME)Dear Secretary Sebelius, Dr. Koh, Dr. Friedan, and Dr. CollinsWe are writing to express our strong concerns with the Department of Health and Human Services (DHHS) current definition activities related to "Chronic Fatigue Syndrome” (“CFS”). We believe DHHS is moving in a direction that is unproductive and harmful to patients. This letter outlines the basis for these concerns and the steps we believe must be taken to rectify the situation.

Throughout the twentieth century, there have been occurrences of a complex, disabling disease characterized by unrefreshing sleep, flu-like symptoms, impairment of memory and other cognitive impairments, orthostatic intolerance, debilitating weakness, pain, fever and the hallmark symptom of post-exertional malaise (post-exertional neuroimmune exhaustion).i This disease has been shown to cause severe dysfunction of neurological, immune, endocrine and energy production systemsii and, since 1969, has been classified as a neurological disease called myalgic encephalomyelitis (ME) by the World Health Organization.iii The name myalgic encephalomyelitis is still used elsewhere and is used herein to refer to this disease and to clearly distinguish it from the non-specific term “CFS”.

Following the outbreak in Incline Village, the CDC named the disease chronic fatigue syndrome (CFS) instead of myalgic encephalomyelitis and developed the first of a number of fatigue-focused case definitions. Today, the term “ME” is rarely used in the U.S. and instead, ME patients are almost always given a diagnosis of CFS.iv

Unfortunately, according to the CDC website, “CFS” can be defined by at least 5 disparate CFS definitions (see Table 1). Three of these, the 2003 Canadian Consensus Criteria, the 2011 ME International Consensus Criteria, and the Pediatric definition, describe the essential and hallmark features of ME. But the two most commonly used definitions, the 1994 Fukuda and 1991 Oxford definitions, focus on fatigue, do not require core ME symptoms like post-exertional malaise, cognitive problems and unrefreshing sleep and allow the inclusion of primary psychiatric illness. In fact, Oxford does not require any symptoms except for 6 months of disabling fatigue for a patient to be given a diagnosis of CFS.

As a result, the term “CFS” has become an amorphous umbrella associated with a diverse set of unrelated conditions that include depression, deconditioningv, medically unexplained chronic fatigue, school phobia, and for some researchers and clinicians, fatigue due to “excessive rest”vi or “false illness beliefs”.vii In clinical practice, doctors give a CFS diagnosis to a heterogeneous mix of patients – those with ME, those with the varied conditions listed above, those who have been misdiagnosed or those whose doctors use CFS as a catchall diagnosis for fatigue.

ME is unquestionably a complex disease and its heterogeneity is real. But this “heterogeneity” is a manufactured artifact of the amalgamation of diverse definitions and unrelated patient populations into one clinical entity called “CFS”. Tragically for ME patients, this has obscured ME in a “web of confusion”,viii which has confounded ME research, virtually precluded drug development and resulted in widely divergent prevalence estimates. This confusion has also negatively impacted clinical care, led to inappropriate and sometimes harmful “one size fits all” clinical guidelines applied to all “CFS” patients and created a climate in which physicians routinely dismiss ME as not real or not serious.There is an urgent need to stop perpetuating this confusion and start researching and treating the disease that these patients actually have – myalgic encephalomyelitis.Given the current embrace of these non-specific “CFS” definitions and the failure to directly engage ME patients and ME experts in the current DHHS definition initiatives, we believe that the outcome of these DHHS initiatives will further exacerbate an already intolerable situation.The following steps are necessary in order to move forward with improved research and treatment for patients with ME:

Adopt a disease appropriate case definition: ME, as defined by the Canadian Consensus Criteria (CCC), must be recognized by DHHS and the United States government for the serious and debilitating disease that it is. ME is not a subtype of “CFS”. The CCC must be adopted now as the baseline case definition for this disease. It can be evolved as additional knowledge is gained, the definition is operationalized and markers are validated. We do not need more years of study to fix what is so clearly broken today.

Stop using “CFS”: The terms "Chronic Fatigue Syndrome" and "CFS" must be permanently abandoned along with the overly broad, two-decades old Fukuda and Oxford definitions. By using non-specific criteria that have become associated with such a diverse set of unrelated conditions, these terms and the accompanying definitions have become medically and scientifically meaningless. They are impeding forward progress and DHHS should discontinue their use. DHHS should also discontinue the dissemination of “CFS” clinical information, like the ‘one size fits all’ CDC CFS Toolkit,ix that uses a non-specific disease description and includes clinical findings and recommendations for all patients based on Oxford, Empirical or chronic fatigue studies.

Manage the transition to the Canadian Consensus Criteria: This includes the adoption and proactive dissemination of appropriate medical guidance like the International Association for CFS/ME Primer,x available through DHHS’ Guidelines.gov. It also includes the establishment of a research program focused on ME, updated insurance guidelines for Medicare/Medicaid, the establishment of disability guidelines for ME and similar transition activities. Most importantly, it must include a plan to care for those patients who have received a diagnosis of "CFS” but do not meet the CCC criteria for ME. These individuals should be properly evaluated and diagnosed where possible. If unexplained conditions remain, additional studies will be needed to understand these conditions and establish more appropriate names and definitions. The continued use of the overly broad “CFS” and Fukuda for these patients is not appropriate.

Engage ME stakeholders in the planning and implementation: In keeping with President Obama’s commitment to Open Government, the key stakeholders – ME patients and ME experts – must be engaged in a full and open partnership to plan for and ensure implementation of this change. We are the ones that best understand this disease and will provide valuable input to these activities.

For decades, ME patients have borne the brunt of the failure to correct the flaws with how “CFS” has been defined. We will not accept this situation any longer.

The FDA Stakeholder Workshop has provided a unique opportunity to approach this disease in new ways, starting with the definition. It is time to adopt the Canadian Consensus Criteria as the baseline case definition for ME research and clinical care and move forward from there. Doing so will energize the wheels of research and drug development and begin to directly improve the lives of the many Americans stricken with this devastating disease.

We look forward to partnering with you to make this a reality for patients. We respectfully request a response to our concerns along with an explanation of how ME patients and ME experts will be engaged in this process by June 5, 2013. Do not hesitate to contact us if you need additional information.

In October 2012, the CFS Advisory Committee (CFSAC) recommended that DHHS convene a workshop by December 31, 2012 or as soon as possible thereafter to “reach a consensus for a case definition useful for research, diagnosis and treatment of ME/CFS beginning with the 2003 Canadian Consensus Definition.”xi In recommending the 2003 Canadian Consensus Criteria as a starting point, it is clear that CFSAC was recognizing the disease, ME, as characterized above, and intended to advance a research and clinical definition for ME. The Canadian Consensus Criteria is already in use both clinically and in research, was developed by well known ME experts at the request of Health Canadaxii, has been shown through numerous studies to better describe ME than either Fukuda or Oxford as discussed below and is well respected by both patients and clinicians. For all these reasons, it provides the best option to establish a disease appropriate baseline definition in the short term that can readily be further evolved in partnership with ME experts as additional data, knowledge and experience is gained, and as the definition is further operationalized and biomarkers are validated.xiii

Based on the available information, it is questionable whether CDC and NIH intend to develop a definition specific for ME or instead continue the focus on the more broadly defined CFS umbrella. Further, the NIH and CDC initiatives are both longer-term initiatives that do not address the significant issues that patients – and research - face today and every day as a result of the definitional problems – issues that could be addressed by adopting the Canadian Consensus Criteria now as discussed by CFSAC at the October, 2012 meeting.

The NIH has stated that they intend to establish a research case definition by performing an evidence-based review of the literature. But we do not know whether NIH intends to include all definitions and criteria encompassed by the “CFS” label or whether they will tease apart the different conditions currently lumped together in order to understand the nature of the separate diseases and conditions therein. Other CFS evidence based reviews, including the 2001 Mulrow review from AHRQ,xiv the review included in the 2007 NICE Guidelinesxv and the 2008 Cochrane reviewxvi of CBT have analyzed diverse “CFS” definitions together as one patient group from which conclusions applicable to all could be drawn. However, as discussed below, these definitions and criteria do not represent the same patient population. It is essential that these diverse “CFS” definitions and criteria be separated out. Doing this will require the involvement of ME experts and patients from the beginning. To date, we do not know of any ME clinical and research experts or patients being engaged in the planning of this effort.

The CDC has stated it intends to use the outcome of the multi-site study to address the clinical case definition. The CDC website states that the multi-site study includes CFS, post-infective fatigue and ME patients and “aims to improve how we measure illness domains of CFS”xvii which the CDC says may allow patients to be sub-grouped. There are two primary concerns with this study. First, the first phase of the multi-site study does not include the measures and instruments, like the two-day cardiopulmonary exercise test, immune markers or a valid psychiatric screen, that are needed to demonstrate the hallmark symptom of PEM, to demonstrate known biological markers or to exclude psychiatric disorders. While the second phase of the study will include an exercise test, it is not clear that CDC will follow Snell’s recommendation to use an 2-day exercise test with gas exchangexviii or how the phase 1 participants will then be assessed. Secondly and more deeply concerning, is that the language on the CDC website suggests that CDC may be intending to develop a definition for the broader “CFS” and consider everything else, including ME, a subtype of CFS.

Three other CDC-related issues reinforce the concerns with the multi-site study. First is the CDC’s continued promotion, in the 2013 Medscape “A Case-Based Approach to Chronic Fatigue Syndrome” CME, of the “one size fits all” CDC CFS Toolkit in spite of CFSAC and patient recommendationsxix to remove it. Second is CDC’s placement of CFS in the U.S. ICD-10-CM in the “Symptoms and Signs” chapter as a subcategory of chronic fatigue rather than in the Neurological chapter as designated in ICD-10 by the World Health Organization (WHO) and as recommended numerous times by the CFSAC since 2005.xx

But of greatest concern is the third issue - the statements on the CDC website (as in the CDC CME “Diagnosis and Management of CFS”)xxi that list five different definitions for CFS (Table 1) and state that all five definitions describe similar sets of patients for which a single set of diagnostic and treatment guidelines is appropriate.xxii Three of these definitions describe the essential and hallmark symptoms and dysfunction of ME: the 2003 Canadian Consensus Criteria, the 2011 ME International Consensus Criteria and the 2006 IACFS/ME Pediatric Case Definition. But the two most commonly used definitions — Fukuda developed by CDC and Oxford developed in the UK — do not require the core symptoms of ME and allow the inclusion of primary psychiatric illness except for schizophrenia and a few other definition-specific psychiatric disorders. For its part, Oxford doesn’t require any symptom at all except for six months of disabling fatigue.

As a result, CFS — the diagnosis that ME patients in the United States are given todayxxiii — has come to be associated with deconditioning,xxiv depression or other psychiatric illness,xxv a variety of “medically unexplained” fatiguing conditions, a history of childhood abusexxvi, “excessive rest” xxvii, maladaptive coping stylesxxviii, a DSM 5 categorized mental illness called somatic symptom disorderxxix and, for some clinicians and researchers, “fear of movement”xxx or “false illness beliefs” that should be treated with cognitive behavioral therapy (CBT) as asserted in the PACE trial, an Oxford definition study.xxxi Any of these diverse patients may be given a diagnosis of CFS.

While not listed as one of the five definitions in the CDC “Diagnosis and Management of CFS” CME, there is also a sixth definition, the 2005 Reeves Empirical definitionxxxii that is the basis of the upper prevalence estimate of 4 million Americans used by the CDC.xxxiii Dr. Leonard Jason of DePaul University showed that the Empirical definition resulted in a tenfold increase over earlier prevalence estimatesxxxiv and led to 38% of major depressive disorder patients being misclassified as CFS.xxxv When asked by Dr. Jason about the continued publication of Empirical studies at the November 2011 CFSAC meeting, CDC’s Dr. Beth Unger said that CDC had done a study comparing approaches and found that “the patient populations are quite comparable.”xxxvi

As patients, we disagree with the assertion that these “CFS” definitions represent the same patients and that these patient populations are comparable. ME experts concur. In a study involving 143,000 patients in the UK, Dr. Luis Naculxxxvii of the London School of Hygiene and Tropical Medicine found a prevalence of 0.19% for patients meeting Fukuda criteria but only a prevalence of 0.11% for those meeting the Canadian Consensus Criteria – almost one half of that of Fukuda. He further stated that symptoms related to issues like neurocognitive and immunological dysfunction were significantly greater in those meeting the Canadian Consensus Criteria. Dr. Bruce Carruthers, an ME expert, has reported “Some symptoms of the Fukuda criteria overlap with depression, whereas the Canadian Consensus Criteria differentiate patients with ME from those who are depressed and identify patients who are more physically debilitated and have greater physical and cognitive functional impairments.”xxxviii

Jason concurs that Fukuda symptoms - chronic fatigue plus unrefreshing sleep, joint pain, muscle pain and impairment in concentration – overlap with depression xxxix He also agrees that the Canadian Consensus Criteria select “a group of patients that have more severe functional impairments, and physical and cognitive symptoms” than Fukuda.xlxli Dr. Michael Maes of Maes Clinics in Thailand has used data mining to demonstrate that Fukuda has two qualitatively different types of patients within it – those with PEM and those without – and showed that the roughly 50% of Fukuda CFS patients with the hallmark PEM also had more severe illness, more severe feelings of infection, greater neurocognitive impairment, and significantly higher levels of immune-inflammatory variables.xlii He concluded that Fukuda CFS patients with PEM and Fukuda CFS patients without PEM “should be considered different case definitions.”xliii In a 2012 review of the definitional criteria for CFS, Yvonne Christley maintained “The differing approaches to the identification and definition of CFS are potentially compounding and strengthening associations between CFS and psychiatric disorders by taking too broad an approach to case identification.”xliv

This takes us to the heart of the problem: ME criteria mixed in with overly broad, non-specific definitions that allow primary psychiatric illness; heterogeneous patient populations identified and studied as one condition called CFS; and sloppy, inappropriate naming that interchangeably uses the terms “CFS”, “CFS/ME”, “ME/CFS”, “ME” and even just “chronic fatigue”. The resultant confusion has severely impacted ME research, drug development and clinical care and misled the medical community on the very nature of ME. Carruthers stated it simply “Patient sets that include people who do not have the disease [ME] lead to biased research findings, inappropriate treatments and waste scarce research funds.“xlv

Dr. Jason agrees. “Such blurring of diagnostic categories will make it even more difficult to identify biological markers for this illness, and if they are not identified, many scientists will be persuaded that this illness is psychogenic.”xlvi FDA’s Dr. Sandra Kweder, in a teleconference with ME patients, acknowledged that the failure to “define the condition well” discourages drug development investment by pharmaceutical companies.xlvii

Beyond the impact on research and drug development is the impact on clinical guidance. Clinical guidance, including that from CDC, uses findings from studies based on any of these definitions and applies them indiscriminately to all patients labeled “CFS”. The prevalence estimates and findings of maladaptive coping skills, mentioned above, are two examples. Other examples include the CDC recommendations for cognitive behavioral therapy (CBT) and graded exercise therapy (GET), provided in spite of patient reports of harm from these therapiesxlviii and even though the supporting studies, like PACE, used Oxford definition. PACE, whose claim of recovery is contested because of how it was measured,xlix did claim that CBT and GET were equally effective in patients that met other criteria for CFS and MEl. However, the CFS definition referenced was the Reeves definition for CFS, diluted to only require the presence of any four symptoms for only one week instead of six months. The criteria for ME patients was a modified version of the infrequently used London criteria, instead of the more commonly accepted Canadian Consensus Criteria. Such loose application of the definitional criteria in a study as widely publicized as PACE only helps to magnify the confusion on the nature of ME and its appropriate treatment.

Most tragically for ME patients, their doctors too often do not understand their disease or do not even believe that it is real.li Putting a sharp point on the depth of misunderstanding, Dr. Klimas stated "I've had patients who met post-traumatic stress disorder criteria... where their trauma was their interaction with their physician around this illness. They came to a doctor with Chronic Fatigue Syndrome; they left the doctor with PTSD."lii This misunderstanding has been fueled by conflicting study findings resulting from the disparate definitions and by the broad-based publicity covering trials like PACE. A third significant contributor is the educational outreach of CDC and Health Resources and Services Administration (HRSA) using clinical guidance materials like the CDC CFS Toolkit, which even promotes the use of the same guidance for “CFS-like” illness, defined as 6 months of fatigue but without all four symptoms required by Fukuda.liii Given these factors, it is not surprisingly that a CDC study of CFS knowledge among health care providers found that 85% of healthcare providers felt that CFS was either partly or completely a psychiatric illness.liv

Such grave misperceptions are seen widely in the medical literature.lv In the 2012 American Family Physician article, Dr. Joseph Yancey listed Oxford and Fukuda as the appropriate definitions and stated “patients with poor social adjustment, a strong belief in an organic cause for fatigue, or some sort of sickness benefit (i.e., financial incentive) tend to have worse responses to [cognitive behavioral] therapy.”lvi Further, a 2013 IOM report on Gulf War Illnesslvii stated that CFS is also called myalgic encephalomyelitis and listed Fukuda and the NICE criterialviii from Britain as the appropriate definitions. Like Fukuda, NICE does not require the core symptoms of ME. Finally, the same misperception on the nature of ME was evident at the Ampligen FDA Advisory Committee when committee member Dr. Sean Hennessey asked how the efficacy of Ampligen compares to the efficacy of cognitive behavioral therapy.lix Would the same question have been asked of a drug for multiple sclerosis or cancer?

We acknowledge that multiple research and clinical case definitions can exist for a given disease and can evolve over time as they have in other diseases. But this is very different. Here, the disease known as ME has virtually disappeared and in its place, CFS has been established as the clinical entity; an entity that is in reality a heterogeneous collection of medically unexplained and often unrelated fatiguing conditions. ME should never have been merged into this group to begin with and should certainly not be considered a subtype of this group.

There is undoubtedly value in having a framework for studying fatigue across diseases. Unfortunately, because Fukuda established a framework that first eliminated fatigue due to known causes like cancer, the opportunity to gain the types of insights seen in a recent study comparing markers in cancer with those in chronic fatigue syndromelx is minimized. But even with the best framework, study of a common symptom like fatigue or pain across diseases can never substitute for the study of the disease itself, using a disease appropriate definition. As Carruthers stated in the ME International Consensus Criteria, “Research on other fatiguing illnesses, such as cancer and multiple sclerosis, is done on patients who have those diseases. There is a current, urgent need for ME research using patients who actually have ME.”lxi Similarly, there is a current, urgent need for treatments and clinical care guidelines appropriate for this disease and a critical need for patients to have access to doctors who believe that they are really sick.

That leaves the question of what to do about the clinical entity called “CFS” once ME patients are pulled out. This complicated issue needs to be carefully managed. First, it is likely that some of these “CFS” patients have been misdiagnosed. They need to receive an appropriate diagnosis. Second, if Maes is correct in saying that it is possible to use inflammatory markers to distinguish between chronic fatigue patients (essentially Oxford) on the one hand and ‘no-PEM’ Fukuda CFS patients on the other, then it is mandatory that these “no-PEM” Fukuda CFS patients also be pulled out, leaving only the symptom of chronic fatigue (equivalent to Oxford CFS), a symptom that can be seen in many illnesses.lxii This further calls into question the validity and utility of the “CFS” construct as a framework for studying medically unexplained fatiguing illnesses. Finally, the literature base associated with all these definitions has become hopelessly intertwined through the use of the same labels across these diverse definitions. Continuing to use the term “CFS” for all or a portion of these conditions will only confound forward progress for all. For these reasons, the entity “CFS” should be dismantled as part of the plan to resolve the definitional problems and develop more appropriate and precise definitions and names for the conditions currently all named “CFS."

References

i The Canadian Consensus Criteria (CCC) uses the term post-exertional malaise (PEM) and the ME International Consensus Criteria (ME-ICC) uses the term post-exertional neuroimmune exhaustion to refer to post-exertional fatigability.ii There are numerous peer-reviewed articles that characterize this disease and the associated dysfunctions. Selected examples of these references include the following:

iii The World Health Organization classified ME as a neurological disease in the ICD-9. CFS did not exist in ICD-9 but was added to the ICD-9-CM in the Signs and Symptoms chapter. WHO added CFS to the neurological diseases category at G93.3 in ICD-10. However, the U.S added CFS to the “Signs and Symptoms” chapter in ICD-10-CM, the same chapter where it was placed in ICD-9-CM. Placement of “CFS” in this chapter is not in compliance with WHO and only further exacerbates medical provider confusion about the nature of the disease.

iv ICD-9-CM Coordination and Maintenance Committee Meeting Summary of Volumes 1 and 2, Diagnosis Presentations September 14, 2011. Page 2. http://www.cdc.gov/nchs/data/icd9/2011SeptemberSummary.pdf. The moderator polled the audience and there was general agreement, by those in the audience, that the term “myalgic encephalomyelitis” is not seen in medical records.

v Joyner, M. Standing up for exercise: should deconditioning be medicalized? August 1, 2012 The Journal of Physiology, 590, 3413-3414. http://jp.physoc.org/content/590/15/3413.fullvi Pariante, C. In his December 2012 pre-publication review of “A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior” by Morris, G., Anderson, G., Galecki, P., Berk, M. and Maes, M. published in BMC Medicine2013, 11:64. Pariante states “For many, including this reviewer, CFS/ME is predominantly a condition triggered by excessive rest in predisposed individuals following acute triggers, and its interpretation requite a psychosocial and psychiatric framework.”

The IACFS/ME is an international organization of clinicians and researchers involved in the study of ME/CFS and the clinical care of patients with ME/CFS. The primer was developed by them and published it in 2012. They are currently working on an updated version of the Primer.xi October 2012 CFSAC recommendation on the case definitionhttp://www.hhs.gov/advcomcfs/recommendations/10032012.html

xiii As reported by panelists at the recent FDA meeting, there are a number of known markers in use today like VO2Max and natural killer cell function that could be readily validated. Regarding patient reported symptoms, Jason has published extensively on the need to have instruments that are validated for the specific definition and that assess not just symptom presence but also symptom severity and frequency.

xvi Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults (Review). Cochrane Database Syst Rev. 2008 Jul 16, http://www.ncbi.nlm.nih.gov/pubmed/18646067,http://www.cfids-cab.org/rc/Price.pdf. The review states that all participants had fatigue as their main or major complaint for at least 3,6 or 12 months. Beyond fatigue, inclusion criteria were heterogeneous. Some studies used Fukuda, some used Oxford, some used the Australian criteria and one study that used Fukuda dropped Fukuda’s requirement for four symptoms.xvii CDC Multi-site Clinical Assessment of CFS http://www.cdc.gov/cfs/programs/clinical-assessment/index.htmlxviii At the FDA ME and CFS stakeholder meeting, Dr. Chris Snell compared the various exercise tests and stated the problems with indirect measures and the importance of using a test that measures gas exchange. He also showed that single exercise tests could not distinguish between deconditioning and ME.http://www.tvworldwide.com/events/fda/130425/ - Panel 3 about minute 75 - 84xix On June 14, 2012, the CFSAC recommended that “the Secretary asks the CDC to take the Toolkit down off the website.” On Sept 10, 2012, the patient community submitted a position paper supporting the CFSAC recommendation and outlining the issues with the Toolkit and the negative impact the Toolkit has had on patients. At the October 2012 CFSAC meeting, in response to Mr. Krafchick’s question on whether the Toolkit would be removed, Dr. Unger replied that it would not be removed. On April 19, 2013, Medscape released the “A Case-Based Approach to Chronic Fatigue Syndrome” CME which recommended the CDC CFS Toolkit as a useful resource. It is not. The Toolkit is a “one size fits all” clinical guideline, that also claims to be suitable for patients with “CFS-like’ illness, defined as fatigued for 6 months without the other symptoms of Fukuda. The information in the Toolkit is not useful and is potentially harmful for patients with ME. See these references for further information:

xx In the draft version of the ICD-10-CM, the National Center for Health Statistics (NCHS) within the CDC has placed CFS in the “Signs and Symptoms” category under chronic fatigue. CFSAC has consistently recommended (as early as August of 2005) that CFS be classified as a neurological disease in compliance with WHO’s ICD-10. The Coalition 4 ME/CFS presented a proposal to NCHS in September of 2011 and again in September of 2012 asking the NCHS to comply with these recommendations and move CFS back to the neurological category. To date, CFS is still listed in “Signs and Symptoms” in ICD-10-CM and unless it is changed by June 2013, CFS will be listed under Signs and Symptoms when ICD-10-CM is published in October 2014. Given this and CDCs continued embrace of CFS as the overly broad collection of fatiguing illnesses as evidenced by the inclusion of Oxford (essentially chronic fatigue), it is clear that the CFS umbrella needs to be broken apart and ME classified as a separate disease.

xxii The CDC CFS Toolkit states that one set of clinical guidelines is suitable for CFS patients and CFS-like illness (6 months of fatigue but does not meet the rest of the symptom requirements for CFS). Other documents, like the 2012 CDC “Diagnosis and Management CFS” CME referenced above also give a single set of guidelines for all 5 definitions. http://www.cdc.gov/cfs/toolkit/index.html

xxiv Joyner, M. Standing up for exercise: should deconditioning be medicalized? August 1, 2012 The Journal of Physiology, 590, 3413-3414. http://jp.physoc.org/content/590/15/3413.full

xxv Every ME patient tells of doctors who have insisted they are depressed, not physically sick - even today in 2013. A number of references in this paper speak to this issue, which is also highlighted in the following extract from Griffith, J., Zarrouf, F. A Systematic Review of Chronic Fatigue Syndrome: Don't Assume It's Depression. Prim Care Companion J Clin Psychiatry. 2008; 10(2): 120–128)

“She is depressed,” her physician wrote when referring Ms. A, a 65-year-old married woman, for a psychiatric consult. “She has been feeling tired for more than a year and described being exhausted most of the time, with headaches, joint pain, and problems with her concentration and memory. Her fatigue is frustrating for her and for her family; she cannot function well even in the morning. She denied being depressed, and does not have any previous mental or medical illnesses. Every lab I checked was normal. I still think that she is hiding her depression and manifesting it with all these somatic complaints.”

xxvi CDC CFS Website, “Childhood Adversity as a Risk Factor for Adult CFS” http://www.cdc.gov/cfs/news/features/childhood_adversity.htmlxxvii Pariante, C. In his December 2012 pre-publication review of “A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior” by Morris, G., Anderson, G., Galecki, P., Berk, M. and Maes, M.published in BMC Medicine2013, 11:64. Pariante states “For many, including this reviewer, CFS/ME is predominantly a condition triggered by excessive rest in predisposed individuals following acute triggers, and its interpretation requite a psychosocial and psychiatric framework.”

xxviii Natera, U., Maloneya, E., Linb, J., Heimc, C., Reeves, W. “Coping Styles in Chronic Fatigue Syndrome: Findings from a Population-Based Study”. Psychother Psychosom 2012;81:127–129.http://www.alphagalileo.org/ViewItem.aspx?ItemId=121978&CultureCode=enxxix Somatic Symptom Disorder (SSD) in the DSM-5, due to be released in May, 2013, can be diagnosed for any patient that meets the following criteria as determined by the health care provider:

a) somatic symptoms that are distressing or significantly disrupt life

b) an excessive concern with the medical seriousness of his or her symptoms

Brown et al examined the ME-ICC and the Fukuda and found that the ME-ICC identified a much tighter group of patients (39 compared to 113 for Fukuda) with more functional impairments and physical, mental and cognitive problems than in those patients meeting the Fukuda criteria. The paper also raised a concern that ME-ICC included more psychiatric co-morbidities than Fukuda because of the number of symptoms required and concluded that a focus on a smaller number of hallmark symptoms like post-exertional malaise would be critical. Finally, the paper acknowledges the need for more study because this study used a questionnaire designed for Fukuda CFS, that they were unable to assess one of the key ME-ICC criteria because of the available data and the study did not look at homebound or bedbound patients. Such study will help to refine the CCC over time.

xlix A number of patients and researchers have contested the PACE claims of recovery. Further, at the FDA ME and CFS stakeholder meeting, Dr. Chris Snell discussed the use of the exercise tests in the PACE trial. http://www.tvworldwide.com/events/fda/130425/ - Panel 3 about minute 70-75

The recent publication from PACE states that they analyzed the data using ME criteria and the International (CDC) criteria. The International criteria was referenced as the Reeves 2003 publication “Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution” This is one of the publications that led to the Empirical definition. Further, they only required that patients had the symptoms for 1 week prior to assessment, not 6 months, to qualify for a diagnosis of CFS. Regarding the ME criteria, they used a 1994 report from Westcare for the ME diagnosis. It is not clear why they did not use Fukuda, why they only required 1 week and why they did not use the much more widely accepted Canadian Consensus Criteria or the newer ME International Consensus Criteria.

In addition to using modified versions of criteria that were either largely abandoned or seldom used to begin with, the PACE trial also used measures of recovery that are broadly disputed by the patient community. It remains to be seen how the research community will respond to the latest PACE paper but it is important to note that PACE style CBT and GET have been rejected by a number of researchers and clinicians as well as by the IACFS/ME Primer (http://www.iacfsme.org/Portals/0/PDF/PrimerFinal3.pdf - p23 for CBT comments.)

li Every patient tells stories of doctors who told them they were depressed, dismissed their illness as made up, refused to treat them or recommended treatments that were inappropriate or harmful for ME/CFS patients. The sheer prevalence of these stories is evidence enough that there is a serious issue. The following references highlight these issues: Bernhard, T. The Stigma of Chronic Fatigue Syndrome. April 10, 2011 http://www.psychologytoday.com/blog/turning-straw-gold/201104/the-stigma-chronic-fatigue- syndromeBernhard, T. The Stigma of Chronic Fatigue Syndrome II: Readers Respond. May 6, 2011http://www.psychologytoday.com/blog/turning-straw-gold/201105/the-stigma-chronic-fatigue- syndrome-ii-readers-respondMontoya, J. Stanford University talk on Chronic Fatigue Syndrome, March 11, 2011 - http://www.youtube.com/watch?v=Riybtt6SChU Minute 6.50 – 7:30 Dr. Montoya said “it is my dream that our medical community will produce a formal apology to patients for not having believed them all these years that they were facing a real illness.”

liii The CDC CFS Toolkit uses Fukuda as the basis of disease description and diagnosis and as stated above, also states that one set of clinical guidelines are suitable for CFS patients and CFS-like illness (6 months of fatigue but does not meet the rest of the symptom requirements for CFS.)http://www.cdc.gov/cfs/toolkit/index.html

lv There are many examples of this misperception in the literature over the years. Some of these are current publications such as the referenced publication by Yancey. Others are older as is this example from Nisenbaum. Unfortunately, it is impossible to tell whether the authors of these older studies still support these statements or not.

Nisenbaum, R. Jones, J., Unger, E., Reyes, M., Reeves, W. A population-based study of the clinical course of chronic fatigue syndrome. Health Qual Life Outcomes. 2003; 1: 49. 2003 October 3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC269990/ This study states “Patients who recovered or improved were younger, did not have a co-morbid psychiatric disorder, and did not believe that the illness was due to a physical cause.”

lix FDA Arthritis Advisory Committee Hearing on Ampligen. Dec 20, 2012 at 2 hours 19 minutes.http://www.fdatracker.com/2012/12/20/20121220-fda-arthritis-advisory-committee-meeting-webcast-audio-recording-heb-ampligen/. Dr. Hennessey asked Hemispherix “to summarize the data on cognitive behavioral therapy which I understand to be effective against chronic fatigue.” CBT has been studied most extensively in studies that use the Oxford definition. One of these studies is the highly publicized PACE trial referenced above, which states “CBT was done on the basis of the fear avoidance theory of chronic fatigue syndrome. This theory regards chronic fatigue syndrome as being reversible and that cognitive responses (fear of engaging in activity) and behavioural responses (avoidance of activity) are linked and interact with physiological processes to perpetuate fatigue.” The PACE trial report states that the aim of CBT is “to change behavioural and cognitive factors assumed to be responsible for perpetuating symptoms and disability” and claims that CBT as a therapy leads to recovery. Yancey’s statement that patients that believe they have an organic illness have the poorer response to therapy was referring to CBT as the therapy.

The fatigue is severe, disabling and affects physical and mental functioning the symptom of fatigue should have been present for a minimum of 6 months during which it was present for more than 50% of the time

Other symptoms may be present, particularly myalgia, mood and sleep disturbance

Chronic Fatigue Syndrome: A Treatment Guide, 2nd Edition (electronic) is now available on Barnes & Noble, Kobo, and Payhip (PDF) in addition to Amazon. If you are in Canada, this is good news!

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About me:I'm a 25-year veteran of CFIDS. I know what it is like to be bedbound for long stretches of time. I also know what it is like to recover, and to relapse. But this blog is not about my personal experience. It is intended to be a resource - a collection of anything that might be helpful to the CFIDS community: book reviews, advice, CFIDS news, research, advocacy, opinion, who's who in our community, fundraising... and occasionally a bit of humor.

Disclaimer: I am not a doctor, which means nothing I write, no matter how sensible it may be, should be interpreted as medical advice.